Is AR p.Ala412Glu (c.1235C>A) pathogenic?

AR p.Ala412Glu (c.1235C>A) is classified Conflicting classifications of pathogenicity in AR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-05-29). AlphaMissense: likely benign (0.292); Ultra-rare (popmax 0.0295%, nfe); Associated with Kennedy disease.

What condition is associated with AR p.Ala412Glu (c.1235C>A)?

AR p.Ala412Glu (c.1235C>A) is associated with Kennedy disease, androgen insensitivity syndrome (ClinVar).

How common is AR p.Ala412Glu (c.1235C>A) in the general population?

AR p.Ala412Glu (c.1235C>A) is ultra-rare (popmax 0.0295%, 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.Ala412Glu (c.1235C>A)?

AlphaMissense predicts likely benign (score 0.292) — an in-silico prediction, not a clinical call.

AR p.Ala412Glu

c.1235C>A · rs762550472 · VCV2469054

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.292 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0295%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Kennedy disease

Computational evidence

Protein change
AlphaMissense	0.292	likely benign
REVEL	0.451	indeterminate
SaProt	LLR -7.20	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 0.49	GERP -2.5, phastCons 0.054
Overall
CADD	13.19	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 0.0295% European (non-Finnish) · 260/881,705 alleles

Filtering AF 0.0265% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0254%

Overall 0.023% 272/1,181,780 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0295%	3,391
Remaining individualsnot grpmax-eligible	0.0237%	4,223
African / African-American	0.00177%	56,576

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.Ala412Glu
Coding: c.1235C>A
MANE Select: NM_000044
dbSNP: rs762550472
Type: single nucleotide variant
Location: chrX:67546381 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 412: 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-ala412glu (accessed [today's date]).

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