Is AR p.Pro218= (c.654C>T) pathogenic?

AR p.Pro218= (c.654C>T) is classified Benign/Likely benign in AR (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-14). Rare (popmax 0.187%, sas); Associated with androgen insensitivity syndrome.

What condition is associated with AR p.Pro218= (c.654C>T)?

AR p.Pro218= (c.654C>T) is associated with androgen insensitivity syndrome, Kennedy disease (ClinVar).

How common is AR p.Pro218= (c.654C>T) in the general population?

AR p.Pro218= (c.654C>T) is rare (popmax 0.187%, sas) (gnomAD).

AR p.Pro218=

c.654C>T · rs751027309 · VCV377498

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.187%, sas)

Conditions

androgen insensitivity syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -0.28, phastCons 0.013
Overall
CADD	6.512	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.187% South Asian · 106/56,821 alleles

Filtering AF 0.158% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.147%

Overall 0.00925% 112/1,210,796 alleles · rare exomes 102/1,098,125 · genomes 10/112,671 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.187%	536
Middle Eastern	0.023%	4,351
Remaining individualsnot grpmax-eligible	0.0084%	11,907
East Asian	0.00297%	33,723

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.Pro218=
Coding: c.654C>T
MANE Select: NM_000044
dbSNP: rs751027309
Type: single nucleotide variant
Location: chrX:67545800 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 218: 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: 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-pro218 (accessed [today's date]).

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