Is AR p.Arg753Ter (c.2257C>T) pathogenic?

AR p.Arg753Ter (c.2257C>T) is classified Pathogenic in AR (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-07-04). Very rare (popmax 0.000223%, nfe); Associated with androgen insensitivity syndrome.

What condition is associated with AR p.Arg753Ter (c.2257C>T)?

AR p.Arg753Ter (c.2257C>T) is associated with androgen insensitivity syndrome, Kennedy disease (ClinVar).

How common is AR p.Arg753Ter (c.2257C>T) in the general population?

AR p.Arg753Ter (c.2257C>T) is very rare (popmax 0.000223%, nfe) (gnomAD).

AR p.Arg753Ter

c.2257C>T · rs886039558 · VCV265460

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000223%, nfe)

Conditions

androgen insensitivity syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 8
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.085	GERP -3.7, phastCons 0.89
Overall
CADD	36.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000223% European (non-Finnish) · 2/895,475 alleles

Filtering AF 3.7e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.4e-05%

Overall 0.000182% 2/1,097,999 alleles · very rare

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.Arg753Ter
Coding: c.2257C>T
MANE Select: NM_000044
dbSNP: rs886039558
Type: single nucleotide variant
Location: chrX:67717561 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 753: the nr lbd domain; the 'interaction with ccar1' region; the 'interaction with kat7' region; a UniProt-annotated variant site (in ais); a binding site; an α-helix; the 'interaction with lpxn' 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 p.Arg753Gln Pathogenic/Likely pathogenic ★★ same residue
AR p.Arg753Leu Likely pathogenic ★ 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-arg753ter (accessed [today's date]).

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