Is AR p.Ser176Arg (c.528C>A) pathogenic?

AR p.Ser176Arg (c.528C>A) is classified Benign/Likely benign in AR (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-05-28). AlphaMissense: ambiguous (0.3776); Rare (popmax 0.453%, eas); Associated with androgen insensitivity syndrome.

What condition is associated with AR p.Ser176Arg (c.528C>A)?

AR p.Ser176Arg (c.528C>A) is associated with androgen insensitivity syndrome, prostate cancer, hypospadias 1, X-linked (ClinVar).

How common is AR p.Ser176Arg (c.528C>A) in the general population?

AR p.Ser176Arg (c.528C>A) is rare (popmax 0.453%, eas) (gnomAD).

What do computational predictors say about AR p.Ser176Arg (c.528C>A)?

AlphaMissense predicts ambiguous (score 0.3776) — an in-silico prediction, not a clinical call.

AR p.Ser176Arg

c.528C>A · rs777131133 · VCV804018

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3776 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.453%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

androgen insensitivity syndrome

Computational evidence

Protein change
AlphaMissense	0.3776	ambiguous
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -8.00	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 4.6	GERP 1.6, phastCons 1
Overall
CADD	24.5	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 0.453% East Asian · 151/33,369 alleles

Filtering AF 0.394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.371%

Overall 0.0151% 182/1,201,360 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.453%	221
Middle Eastern	0.023%	4,342
Remaining individualsnot grpmax-eligible	0.0211%	4,728
South Asian	0.0163%	6,144
European (non-Finnish)	0.00123%	80,972

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.Ser176Arg
Coding: c.528C>A
MANE Select: NM_000044
dbSNP: rs777131133
Type: single nucleotide variant
Location: chrX:67545674 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 176: the 'interaction with znf318' region; the 'modulating' 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: prostate cancer hypospadias 1, X-linked partial androgen insensitivity syndrome 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-ser176arg (accessed [today's date]).

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