Is AR p.Lys659Arg (c.1976A>G) pathogenic?

AR p.Lys659Arg (c.1976A>G) is classified Conflicting classifications of pathogenicity in AR (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-20). AlphaMissense: likely benign (0.0963); Very rare (popmax 0.0089%, eas); Associated with ovarian cancer.

What condition is associated with AR p.Lys659Arg (c.1976A>G)?

AR p.Lys659Arg (c.1976A>G) is associated with ovarian cancer (ClinVar).

How common is AR p.Lys659Arg (c.1976A>G) in the general population?

AR p.Lys659Arg (c.1976A>G) is very rare (popmax 0.0089%, eas) (gnomAD).

What do computational predictors say about AR p.Lys659Arg (c.1976A>G)?

AlphaMissense predicts likely benign (score 0.0963) — an in-silico prediction, not a clinical call.

AR p.Lys659Arg

c.1976A>G · rs879021764 · VCV2445341

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0963 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0089%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.0963	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -6.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.2	GERP 1.7, phastCons 1
Overall
CADD	22.1	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 0.0089% East Asian · 3/33,721 alleles

Filtering AF 0.00236% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00125%

Overall 0.000662% 8/1,209,298 alleles · very rare exomes 7/1,097,106 · genomes 1/112,192 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0089%	11,240
South Asian	0.00532%	18,811
Remaining individualsnot grpmax-eligible	0.0042%	23,787

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.Lys659Arg
Coding: c.1976A>G
MANE Select: NM_000044
dbSNP: rs879021764
Type: single nucleotide variant
Location: chrX:67711492 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 659: the 'interaction with hipk3' region; the 'interaction with ccar1' region; the 'interaction with kat7' region; the 'interaction with lpxn' region

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

Disease context

ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AR p.Lys659= Likely benign ★ same residue
AR p.Leu57Gln Benign/Likely benign ★★ same condition
AR p.Ser495Asn Benign ★★ same condition
AR p.Ala736Asp Likely pathogenic ★ ⚠ same condition
AR p.Arg386Leu Likely pathogenic ★ ⚠ same condition
AR p.Glu474Gly Likely pathogenic ★ ⚠ same condition
AR p.Gly454Arg Likely pathogenic ★ ⚠ same condition
AR p.Gly396Arg Conflicting classifications of pathogenicity ★ ⚠ 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-lys659arg (accessed [today's date]).

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