ARc.455C>TUncertain significance

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Variant interpretation report

AR c.455C>T, p.(Pro152Leu)

NM_000044.4:c.455C>T NP_000035.2:p.(Pro152Leu) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About AR

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 supporting (benign) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 24 Jun 2026 · version 7.0.0

Evidence considered

View criteria

Applied evidence criteria

PM2 (supporting): Extremely low frequency in population databases. Absent from gnomAD v2.1. Present in gnomAD v4.1 at an allele frequency of 8.42 × 10⁻⁷ (1/1,187,892 alleles; 0 homozygotes), well below the 0.1% PM2 threshold. The single observed allele is in a hemizygous male of European (non-Finnish) ancestry. Absent from gnomAD-Canada v1.0.
BP4 (supporting): Multiple lines of computational evidence suggest no impact on the gene product. BayesDel score = -0.0120934 (negative value, consistent with benign prediction). SpliceAI max delta score = 0.00 (no predicted splicing alteration). REVEL was unavailable; however, the concordance of available in silico tools supports BP4 at supporting level.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1

Pathogenic criteria applied · 1

PM2Supporting

PM2 · supporting

Extremely low frequency in population databases. Absent from gnomAD v2.1. Present in gnomAD v4.1 at an allele frequency of 8.42 × 10⁻⁷ (1/1,187,892 alleles; 0 homozygotes), well below the 0.1% PM2 threshold. The single observed allele is in a hemizygous male of European (non-Finnish) ancestry. Absent from gnomAD-Canada v1.0.

Benign criteria applied · 1

BP4Supporting

BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product. BayesDel score = -0.0120934 (negative value, consistent with benign prediction). SpliceAI max delta score = 0.00 (no predicted splicing alteration). REVEL was unavailable; however, the concordance of available in silico tools supports BP4 at supporting level.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

1 / 1,187,892 alleles

gnomAD v4.1: 1 / 1,187,892 alleles. Recorded AF 8.41827e-07. Recorded homozygote count 0.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. AR (androgen receptor), a transcription factor, is most frequently altered in advanced or castration-resistant prostate cancer.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

27 criteria with recorded statuses: 2 met · 7 not met · 15 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000044.4:c.455C>T (p.Pro152Leu) in AR is a missense variant in the N-terminal transactivation domain.

This variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present in gnomAD v4.1 at an allele frequency of 8.42 × 10⁻⁷ (1/1,187,892 alleles), fulfilling PM2 at supporting strength.

In silico predictions are concordantly benign: BayesDel scores -0.012 (benign range) and SpliceAI predicts no splicing alteration (max delta = 0.00), supporting BP4 at supporting level.

One supporting pathogenic criterion (PM2_supporting) and one supporting benign criterion (BP4_supporting) offset each other. The variant is absent from ClinVar, has no functional data, and no literature reports.

Insufficient evidence to classify as pathogenic or benign. Overall classification: Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 framework.

Met · 2

PM2 SupportingExtremely low frequency in population databases. Absent from gnomAD v2.1. Present in gnomAD v4.1 at an allele frequency of 8.42 × 10⁻⁷ (1/1,187,892 alleles; 0 homozygotes), well below the 0.1% PM2 threshold. The single observed allele is in a hemizygous male of European (non-Finnish) ancestry. Absent from gnomAD-Canada v1.0. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: absent.
gnomAD v4.1: AF = 8.42 × 10⁻⁷ (1/1
187
892 alleles
0 hom).
gnomAD-Canada v1.0: absent.

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. BayesDel score = -0.0120934 (negative value, consistent with benign prediction). SpliceAI max delta score = 0.00 (no predicted splicing alteration). REVEL was unavailable; however, the concordance of available in silico tools supports BP4 at supporting level. Details ▾Hide ▴

Evidence considered

BayesDel: -0.012 (benign range).
SpliceAI max delta: 0.00 (no splice alteration).

Sources

bayesdelspliceai ↗

Not met · 7 · evaluated, threshold not reached

PM1 Variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org). Pro152 resides in the N-terminal transactivation domain of AR, which is not an established critical functional domain with high pathogenic missense constraint. Details ▾Hide ▴

Evidence considered

Not in a statistically significant hotspot
N-terminal domain lacks established critical functional domain criteria.

PP2 PP2 requires a gene with a low rate of benign missense variation and a high proportion of pathogenic missense variants. AR has known pathogenic missense variants predominantly in the ligand-binding domain, but Pro152 resides in the N-terminal transactivation domain where missense constraint is not established. No HCI prior or gene-specific missense constraint metric available to support PP2. Details ▾Hide ▴

Evidence considered

AR missense constraint not established for N-terminal domain
no HCI prior available.

PP3 Multiple lines of computational evidence do not support a deleterious effect. BayesDel score = -0.012 (negative, falls in benign range). SpliceAI max delta = 0.00 (no predicted splicing alteration). REVEL score not available. Without multiple concordant deleterious in silico predictions, PP3 is not met. Details ▾Hide ▴

Evidence considered

BayesDel: -0.012 (benign).
SpliceAI max delta: 0.00 (no splice impact).
REVEL: not available.

Sources

bayesdelspliceai ↗

PP5 Not reported as pathogenic by a reputable source. This variant is absent from ClinVar entirely; no expert panel or clinical laboratory has submitted a pathogenic classification. Details ▾Hide ▴

Evidence considered

Absent from ClinVar
no pathogenic classification from any submitter.

Sources

clinvar ↗

BA1 Allele frequency in gnomAD v4.1 is 8.42 × 10⁻⁷ (0.000084%), far below the BA1 threshold of >1%. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 8.42 × 10⁻⁷
well below 1% BA1 threshold.

Sources

gnomad_v4 ↗

BS1 Allele frequency in gnomAD v4.1 is 8.42 × 10⁻⁷ (0.000084%), far below the BS1 threshold of >0.3%. Details ▾Hide ▴

Evidence considered

gnomAD v4.1 AF = 8.42 × 10⁻⁷
well below 0.3% BS1 threshold.

Sources

gnomad_v4 ↗

BP1 BP1 applies to missense variants in genes where truncating variants are the primary/only disease mechanism. AR missense variants are well-established causes of androgen insensitivity syndrome and other AR-related disorders; therefore, a missense change does not qualify for BP1. Details ▾Hide ▴

Evidence considered

AR has well-characterized pathogenic missense variants
not a gene where only truncating variants cause disease.

Not assessed · 15 · no assessment recorded

PS1 No prior pathogenic variant at this nucleotide position identified. Absent from ClinVar; no literature reports of a pathogenic variant at NM_000044.4:c.455. Details ▾Hide ▴

Evidence considered

Absent from ClinVar
no same-nucleotide pathogenic variant identified.

Still missing

No same-nucleotide comparator in ClinVar or literature.

Sources

clinvar ↗

PS2 No de novo occurrence data available. No family studies or case reports identified for this variant. Details ▾Hide ▴

Still missing

No de novo testing data
no parental genotype information.

PS3 No well-established in vitro or in vivo functional studies identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence. No publications with functional data for NM_000044.4:c.455C>T. Details ▾Hide ▴

Evidence considered

OncoKB: Unknown Oncogenic Effect
no variant-specific functional data.

Still missing

No variant-specific functional studies in the literature.

Sources

oncokb ↗

PS4 No case-control or prevalence data comparing affected individuals to general population controls available. Details ▾Hide ▴

Still missing

No case-control studies
no enrichment data in affected cohorts.

PM5 No pathogenic missense variant at the same amino acid residue (Pro152) identified as a comparator. PM5 candidate harvesting could not find same-residue ClinVar entries; no alternative pathogenic missense at this codon. Details ▾Hide ▴

Evidence considered

No same-residue pathogenic comparator at Pro152 identified.

Still missing

No pathogenic missense at codon 152 for PM5 comparison.

Sources

pm5_candidates

PM6 No de novo occurrence data available. No family studies or case reports with confirmed maternity/paternity identified for this variant. Details ▾Hide ▴

Still missing

No de novo testing data
no confirmed parental genotypes.

PP1 No cosegregation data available. No family studies with multiple affected individuals identified for this variant. Details ▾Hide ▴

Still missing

No family segregation data available.

PP4 No patient phenotype or clinical information provided for this case. Without phenotype data, cannot assess specificity of presentation for AR-related disease. Details ▾Hide ▴

Still missing

Patient phenotype not available for assessment.

BS2 No data on observation in healthy adults with full penetrance expected at an early age. AR-related disorders (e.g., androgen insensitivity syndrome) have variable expressivity and the X-linked inheritance pattern complicates BS2 application without individual-level clinical data. Details ▾Hide ▴

Still missing

No data on healthy adult carriers with expected full penetrance.

BS3 No well-established functional studies showing no damaging effect for this variant. No variant-specific functional data identified in the literature or curated databases. Details ▾Hide ▴

Still missing

No variant-specific functional studies demonstrating benign effect.

BS4 No segregation data available to assess lack of cosegregation with disease in affected families. Details ▾Hide ▴

Still missing

No family segregation data available.

BP2 No data on observation in trans with a pathogenic variant. For X-linked AR, hemizygous males cannot have a trans configuration; in females, X-inactivation patterns and clinical data would be required. Details ▾Hide ▴

Still missing

No trans-phase genotype data available.

BP5 No data on an alternate molecular basis for disease in an individual harboring this variant. Details ▾Hide ▴

Still missing

No alternate molecular diagnosis data available.

BP6 Not reported as benign by a reputable source. This variant is absent from ClinVar; no benign classification from any submitter. Details ▾Hide ▴

Evidence considered

Absent from ClinVar
no benign classification available.

Sources

clinvar ↗

PS5 No alternative pathogenic variant at the same amino acid residue (Pro152) identified. PM5 candidate harvesting could not identify same-residue comparator variants; no alternative missense changes at codon 152 found in ClinVar. Details ▾Hide ▴

Evidence considered

PM5 candidate search found no same-residue pathogenic comparators at Pro152.

Still missing

No pathogenic missense variants at codon 152 identified.

Sources

pm5_candidates

Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AMissense variant (c.455C>T, p.Pro152Leu) does not fall into PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The variant-level generic PVS1 assessment confirms apply_generic_pvs1_framework = false. Details ▾Hide ▴

Evidence considered

Missense substitution
not a predicted null variant.

Sources

pvs1_variant_assessment

BP3 N/AVariant is a single nucleotide substitution, not an in-frame deletion/insertion in a repetitive region. Details ▾Hide ▴

Evidence considered

Substitution variant
BP3 applies only to in-frame indels in repetitive regions.

BP7 N/AVariant is a missense change (c.455C>T, p.Pro152Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution
BP7 applies only to synonymous variants.

Identifiers

Gene: AR
Transcript: NM_000044.4
Coding (HGVS c.): NM_000044.4:c.455C>T
Protein (HGVS p.): NP_000035.2:p.(Pro152Leu)
GRCh38: chrX:67545601 C>T
GRCh37: chrX:66765443 C>T

Gene diagram

Every interpreted variant in AR, mapped onto the exon structure of NM_000044.4. Select a row to find it on the plot.

ARNM_000044.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in AR — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 1 / 1,187,892 alleles AF 8.42e-07 · 0 homozygotes

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 8.4e-07 · 1 / 1,187,892 alleles · 0 hom

European (non-Finnish)1 / 883,379

1.1e-06

0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 8.41827e-07; MAF= 0.00008%, 1/1187892 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.13202e-06; MAF= 0.00011%, 1/883379 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: -0.012

How the predictions were used

Evidence considered

BayesDel: -0.012 (benign range).
SpliceAI max delta: 0.00 (no splice alteration).

Sources

bayesdelspliceai ↗

Evidence considered

BayesDel: -0.012 (benign).
SpliceAI max delta: 0.00 (no splice impact).
REVEL: not available.

Sources

bayesdelspliceai ↗

BP7 N/AVariant is a missense change (c.455C>T, p.Pro152Leu), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴

Evidence considered

Missense substitution
BP7 applies only to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.0120934.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 1 / 1,187,892 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = -0.0120934.

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.