Is AR p.Trp399Arg (c.1195T>C) pathogenic?

AR p.Trp399Arg (c.1195T>C) is classified Pathogenic in AR (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.7381); Very rare (popmax 0.00271%, nfe); Associated with prostate cancer.

What condition is associated with AR p.Trp399Arg (c.1195T>C)?

AR p.Trp399Arg (c.1195T>C) is associated with prostate cancer (ClinVar).

How common is AR p.Trp399Arg (c.1195T>C) in the general population?

AR p.Trp399Arg (c.1195T>C) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about AR p.Trp399Arg (c.1195T>C)?

AlphaMissense predicts likely pathogenic (score 0.7381) — an in-silico prediction, not a clinical call.

AR p.Trp399Arg

c.1195T>C · rs774645775 · VCV1685535

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7381 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

prostate cancer

Computational evidence

Protein change
AlphaMissense	0.7381	likely pathogenic ✓ concordant with ClinVar
REVEL	0.765	pathogenic-leaning
SaProt	LLR -5.32	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Overall
CADD	21.9	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 0.00271% European (non-Finnish) · 24/885,607 alleles

Filtering AF 0.00183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00154%

Overall 0.0145% 172/1,189,568 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.573%	175
Remaining individualsnot grpmax-eligible	0.0492%	2,032
European (non-Finnish)grpmax	0.00271%	36,900
African / African-American	0.00176%	56,878

Ashkenazi Jewish 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.Trp399Arg
Coding: c.1195T>C
MANE Select: NM_000044
dbSNP: rs774645775
Type: single nucleotide variant
Location: chrX:67546341 (GRCh38)
Structure: AlphaFold pLDDT 58.85 · 95 PDB
Residue 399: the 'interaction with znf318' region; the 'modulating' region

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

Disease context

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

Similar variants

AR p.Val867Met Pathogenic ★★ ⚠ same condition
AR p.Gln63Leu Uncertain significance ★★ ⚠ same condition
AR p.Pro342Leu Uncertain significance ★★ ⚠ same condition
AR p.Ser176Arg Benign/Likely benign ★★ ⚠ same condition
AR p.Ala403Val Pathogenic ★ same condition
AR p.Asn728Lys Pathogenic ★ ⚠ same condition
AR p.Gln70Ter Pathogenic ★ same condition
AR c.1885+3718A>G Uncertain significance ★ 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-trp399arg (accessed [today's date]).

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