Is AR p.Ala646Asp (c.1937C>A) pathogenic?

AR p.Ala646Asp (c.1937C>A) is classified Conflicting classifications of pathogenicity in AR (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-01). AlphaMissense: likely benign (0.1766); Rare (popmax 0.267%, nfe); Associated with Kennedy disease.

What condition is associated with AR p.Ala646Asp (c.1937C>A)?

AR p.Ala646Asp (c.1937C>A) is associated with Kennedy disease, male infertility, partial androgen insensitivity syndrome (ClinVar).

How common is AR p.Ala646Asp (c.1937C>A) in the general population?

AR p.Ala646Asp (c.1937C>A) is rare (popmax 0.267%, 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.Ala646Asp (c.1937C>A)?

AlphaMissense predicts likely benign (score 0.1766) — an in-silico prediction, not a clinical call.

AR p.Ala646Asp

c.1937C>A · rs1800053 · VCV9861

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1766 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.267%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Kennedy disease

Computational evidence

Protein change
AlphaMissense	0.1766	likely benign
REVEL	0.58	indeterminate
SaProt	LLR -6.21	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -0.44, phastCons 0.79
Overall
CADD	17.37	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 0.267% European (non-Finnish) · 2,383/891,042 alleles

Filtering AF 0.258% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.255%

Overall 0.205% 2,468/1,202,319 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.267%	374
Remaining individualsnot grpmax-eligible	0.112%	893
Finnishnot grpmax-eligible	0.0411%	2,431
Admixed American	0.0134%	7,482
African / African-American	0.0123%	8,157

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.Ala646Asp
Coding: c.1937C>A
MANE Select: NM_000044
dbSNP: rs1800053
Type: single nucleotide variant
Location: chrX:67711453 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 646: the 'interaction with hipk3' region; a UniProt-annotated variant site (in); the 'interaction with ccar1' region; the 'interaction with kat7' region; the 'interaction with lpxn' 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: male infertility partial androgen insensitivity syndrome Castleman-Kojima disease 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-ala646asp (accessed [today's date]).

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