Is AR p.Arg727Leu (c.2180G>T) pathogenic?

AR p.Arg727Leu (c.2180G>T) is classified Conflicting classifications of pathogenicity in AR (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-02-23). AlphaMissense: likely pathogenic (0.977); Ultra-rare (popmax 0.0106%, nfe); Associated with Kennedy disease.

What condition is associated with AR p.Arg727Leu (c.2180G>T)?

AR p.Arg727Leu (c.2180G>T) is associated with Kennedy disease, prostate cancer, androgen insensitivity syndrome (ClinVar).

How common is AR p.Arg727Leu (c.2180G>T) in the general population?

AR p.Arg727Leu (c.2180G>T) is ultra-rare (popmax 0.0106%, 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.Arg727Leu (c.2180G>T)?

AlphaMissense predicts likely pathogenic (score 0.977) — an in-silico prediction, not a clinical call.

AR p.Arg727Leu

c.2180G>T · rs137852593 · VCV9849

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.977 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0106%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Kennedy disease

Computational evidence

Protein change
AlphaMissense	0.977	likely pathogenic
REVEL	0.951	strongly pathogenic-leaning
SaProt	LLR -11.73	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	27.2	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 0.0106% European (non-Finnish) · 95/895,222 alleles

Filtering AF 0.00886% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00823%

Overall 0.0415% 502/1,210,163 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.821%	122
Remaining individualsnot grpmax-eligible	0.0462%	2,164
European (non-Finnish)grpmax	0.0106%	9,423
South Asian	0.00176%	56,785
African / African-American	0.00174%	57,308

Finnish 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.Arg727Leu
Coding: c.2180G>T
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: prostate cancer androgen insensitivity syndrome

For Kennedy disease (Orphanet):

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

Similar variants

AR p.Arg727His Uncertain significance ★ ⚠ 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-arg727leu (accessed [today's date]).

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