Is AR p.Ala159Thr (c.475G>A) pathogenic?

AR p.Ala159Thr (c.475G>A) is classified Conflicting classifications of pathogenicity in AR (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-12). AlphaMissense: likely benign (0.1491); Ultra-rare (popmax 0.0219%, nfe); Associated with androgen insensitivity syndrome.

What condition is associated with AR p.Ala159Thr (c.475G>A)?

AR p.Ala159Thr (c.475G>A) is associated with androgen insensitivity syndrome, male infertility, Kennedy disease (ClinVar).

How common is AR p.Ala159Thr (c.475G>A) in the general population?

AR p.Ala159Thr (c.475G>A) is ultra-rare (popmax 0.0219%, nfe) (gnomAD).

What do computational predictors say about AR p.Ala159Thr (c.475G>A)?

AlphaMissense predicts likely benign (score 0.1491) — an in-silico prediction, not a clinical call.

AR p.Ala159Thr

c.475G>A · rs370215797 · VCV492777

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1491 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0219%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

androgen insensitivity syndrome

Computational evidence

Protein change
AlphaMissense	0.1491	likely benign
REVEL	0.75	pathogenic-leaning
SaProt	LLR -6.55	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Overall
CADD	26.9	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 0.0219% European (non-Finnish) · 194/884,753 alleles

Filtering AF 0.0194% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0184%

Overall 0.0181% 215/1,189,197 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0341%	2,928
European (non-Finnish)grpmax	0.0219%	4,561
Admixed American	0.00468%	21,369
African / African-American	0.00354%	28,274
Finnishnot grpmax-eligible	0.00223%	44,871

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala159Thr
Coding: c.475G>A
MANE Select: NM_000044
dbSNP: rs370215797
Type: single nucleotide variant
Location: chrX:67545621 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 159: the 'interaction with znf318' region; the 'modulating' region; the 'disordered' region

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

Disease context

androgen insensitivity syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: male infertility Kennedy disease

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-ala159thr (accessed [today's date]).

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