Is AR p.Glu442Val (c.1325A>T) pathogenic?

AR p.Glu442Val (c.1325A>T) is classified Uncertain significance in AR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-09). AlphaMissense: ambiguous (0.4993); Very rare (popmax 0.000114%, nfe); Associated with Kennedy disease.

What condition is associated with AR p.Glu442Val (c.1325A>T)?

AR p.Glu442Val (c.1325A>T) is associated with Kennedy disease, androgen insensitivity syndrome (ClinVar).

How common is AR p.Glu442Val (c.1325A>T) in the general population?

AR p.Glu442Val (c.1325A>T) is very rare (popmax 0.000114%, nfe) (gnomAD).

How is Kennedy disease inherited?

Typically X-linked recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AR p.Glu442Val (c.1325A>T)?

AlphaMissense predicts ambiguous (score 0.4993) — an in-silico prediction, not a clinical call.

AR p.Glu442Val

c.1325A>T · rs772400835 · VCV2935018

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4993 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000114%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Kennedy disease

Computational evidence

Protein change
AlphaMissense	0.4993	ambiguous
REVEL	0.693	pathogenic-leaning
SaProt	LLR -7.44	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Overall
CADD	24.7	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 0.000114% European (non-Finnish) · 1/876,665 alleles

Overall 8.53e-05% 1/1,172,293 alleles · very rare exomes 1/1,063,214 · genomes 0/109,079 · joint denominator

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.Glu442Val
Coding: c.1325A>T
MANE Select: NM_000044
dbSNP: rs772400835
Type: single nucleotide variant
Location: chrX:67546471 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 442: the 'interaction with znf318' region; the 'modulating' region

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

Disease context

Kennedy disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: androgen insensitivity syndrome

For Kennedy disease (Orphanet):

Inheritance: X-linked recessive
Onset: Adult
Prevalence: <1 / 1 000 000 (Italy)

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-glu442val (accessed [today's date]).

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