Is AR p.Ala475Val (c.1424C>T) pathogenic?

AR p.Ala475Val (c.1424C>T) is classified Conflicting classifications of pathogenicity in AR (ClinVar, Conflicting submitters, 12 submitters; last evaluated 2026-09-06). AlphaMissense: likely benign (0.1235); Rare (popmax 0.781%, mid); Associated with hypospadias 1, X-linked.

What condition is associated with AR p.Ala475Val (c.1424C>T)?

AR p.Ala475Val (c.1424C>T) is associated with hypospadias 1, X-linked, male infertility, partial androgen insensitivity syndrome (ClinVar).

How common is AR p.Ala475Val (c.1424C>T) in the general population?

AR p.Ala475Val (c.1424C>T) is rare (popmax 0.781%, mid) (gnomAD).

What do computational predictors say about AR p.Ala475Val (c.1424C>T)?

AlphaMissense predicts likely benign (score 0.1235) — an in-silico prediction, not a clinical call.

AR p.Ala475Val

c.1424C>T · rs200390780 · VCV804019

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.1235 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.781%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hypospadias 1, X-linked

Computational evidence

Protein change
AlphaMissense	0.1235	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -7.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 1.2
Overall
CADD	16.69	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.781% Middle Eastern · 25/3,199 alleles

Filtering AF 0.543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.464%

Overall 0.214% 2,167/1,012,309 alleles · rare exomes 2,046/911,883 · genomes 121/100,426 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.781%	128
South Asian	0.408%	245
European (non-Finnish)	0.242%	412
Remaining individualsnot grpmax-eligible	0.224%	447
Finnishnot grpmax-eligible	0.0264%	3,786
African / African-American	0.0228%	4,376
Admixed American	0.0176%	5,672
East Asian	0.00804%	12,431

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: AR
Protein: p.Ala475Val
Coding: c.1424C>T
MANE Select: NM_000044
dbSNP: rs200390780
Type: single nucleotide variant
Location: chrX:67546570 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 475: the 'interaction with znf318' region; the 'modulating' region

Full AR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypospadias 1, X-linked — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: male infertility partial androgen insensitivity syndrome Kennedy disease androgen insensitivity syndrome prostate cancer, hereditary, X-linked 3

Similar variants

AR c.1768+2T>C Pathogenic/Likely pathogenic ★★ same condition
AR c.1769-11T>A Pathogenic ★★ same condition
AR c.2450-6C>G Pathogenic ★★ same condition
AR p.Ala588Pro Pathogenic/Likely pathogenic ★★ same condition
AR p.Ala597Thr Pathogenic ★★ same condition
AR p.Ala688Val Pathogenic/Likely pathogenic ★★ same condition
AR p.Ala766Thr Pathogenic ★★ same condition
AR p.Ala871Val Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ar-p-ala475val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown