Is AR p.Leu745= (c.2235C>T) pathogenic?

AR p.Leu745= (c.2235C>T) is classified Likely benign in AR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-01). Very rare (popmax 0.00436%, amr); Associated with androgen insensitivity syndrome.

What condition is associated with AR p.Leu745= (c.2235C>T)?

AR p.Leu745= (c.2235C>T) is associated with androgen insensitivity syndrome, Kennedy disease (ClinVar).

How common is AR p.Leu745= (c.2235C>T) in the general population?

AR p.Leu745= (c.2235C>T) is very rare (popmax 0.00436%, amr) (gnomAD).

AR p.Leu745=

c.2235C>T · VCV4782604

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00436%, amr)

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 -0.64	GERP -3.7, phastCons 0.02
Overall
CADD	3.269	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00436% Admixed American · 2/45,922 alleles

Filtering AF 0.000722% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00027%

Overall 0.000661% 8/1,210,630 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00436%	22,961
Remaining individualsnot grpmax-eligible	0.0021%	47,591
African / African-American	0.00174%	57,391
European (non-Finnish)	0.000447%	223,821

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.Leu745=
Coding: c.2235C>T
MANE Select: NM_000044
Type: single nucleotide variant
Location: chrX:67717539 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 745: the nr lbd domain; the 'interaction with ccar1' region; the 'interaction with kat7' region; a UniProt-annotated variant site (in ais and prostate cancer); 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.Leu745Phe 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
AR p.Ala766Thr 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-leu745 (accessed [today's date]).

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