Is AR p.Ala749Val (c.2246C>T) pathogenic?

AR p.Ala749Val (c.2246C>T) is classified Likely pathogenic in AR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-11). AlphaMissense: likely pathogenic (0.9575); Absent from gnomAD v4.1; Associated with disorder of sexual differentiation.

What condition is associated with AR p.Ala749Val (c.2246C>T)?

AR p.Ala749Val (c.2246C>T) is associated with disorder of sexual differentiation (ClinVar).

How common is AR p.Ala749Val (c.2246C>T) in the general population?

AR p.Ala749Val (c.2246C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AR p.Ala749Val (c.2246C>T)?

AlphaMissense predicts likely pathogenic (score 0.9575) — an in-silico prediction, not a clinical call.

AR p.Ala749Val

c.2246C>T · VCV3767296

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9575 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

disorder of sexual differentiation

Computational evidence

Protein change
AlphaMissense	0.9575	likely pathogenic ✓ concordant with ClinVar
REVEL	0.912	moderately pathogenic-leaning
SaProt	LLR -11.72	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 0.92, phastCons 1
Overall
CADD	27.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AR
Protein: p.Ala749Val
Coding: c.2246C>T
MANE Select: NM_000044
Type: single nucleotide variant
Location: chrX:67717550 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 749: the nr lbd domain; the 'interaction with ccar1' region; the 'interaction with kat7' region; a UniProt-annotated variant site (in pais); a UniProt-annotated variant site (in prostate cancer); an α-helix; the 'interaction with lpxn' region

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

Disease context

disorder of sexual differentiation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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

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-ala749val (accessed [today's date]).

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