Is AR p.Arg727His (c.2180G>A) pathogenic?

AR p.Arg727His (c.2180G>A) is classified Uncertain significance in AR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-06). AlphaMissense: likely pathogenic (0.8513); Very rare (popmax 0.00369%, nfe); Associated with Kennedy disease.

What condition is associated with AR p.Arg727His (c.2180G>A)?

AR p.Arg727His (c.2180G>A) is associated with Kennedy disease, androgen insensitivity syndrome (ClinVar).

How common is AR p.Arg727His (c.2180G>A) in the general population?

AR p.Arg727His (c.2180G>A) is very rare (popmax 0.00369%, 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.Arg727His (c.2180G>A)?

AlphaMissense predicts likely pathogenic (score 0.8513) — an in-silico prediction, not a clinical call.

AR p.Arg727His

c.2180G>A · rs137852593 · VCV2936340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8513 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00369%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Kennedy disease

Computational evidence

Protein change
AlphaMissense	0.8513	likely pathogenic
REVEL	0.929	moderately pathogenic-leaning
SaProt	LLR -10.78	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.9, phastCons 1
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00369% European (non-Finnish) · 33/895,229 alleles

Filtering AF 0.00263% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00231%

Overall 0.00297% 36/1,210,110 alleles · very rare exomes 36/1,097,894 · genomes 0/112,216 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00369%	27,128
Finnishnot grpmax-eligible	0.00214%	46,659
Remaining individualsnot grpmax-eligible	0.0021%	47,592
South Asian	0.00176%	56,793

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.Arg727His
Coding: c.2180G>A
MANE Select: NM_000044
dbSNP: rs137852593
Type: single nucleotide variant
Location: chrX:67717484 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 727: the nr lbd domain; the 'interaction with ccar1' region; the 'interaction with kat7' region; a UniProt-annotated variant site (in hpcx3); an α-helix; 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: androgen insensitivity syndrome

For Kennedy disease (Orphanet):

Inheritance: X-linked recessive
Onset: Adult
Prevalence: <1 / 1 000 000 (Italy)

Similar variants

AR p.Arg727Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
AR p.Arg727Cys Benign ★ same residue
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

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-arg727his (accessed [today's date]).

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