Is STS p.Arg269Trp (c.805C>T) pathogenic?

STS p.Arg269Trp (c.805C>T) is classified Conflicting classifications of pathogenicity in STS (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-11). AlphaMissense: likely benign (0.1524); Ultra-rare (popmax 0.021%, afr).

How common is STS p.Arg269Trp (c.805C>T) in the general population?

STS p.Arg269Trp (c.805C>T) is ultra-rare (popmax 0.021%, afr) (gnomAD).

What do computational predictors say about STS p.Arg269Trp (c.805C>T)?

AlphaMissense predicts likely benign (score 0.1524) — an in-silico prediction, not a clinical call.

STS p.Arg269Trp

c.805C>T · rs146117456 · VCV2155041

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1524 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.021%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1524	likely benign
REVEL	0.455	indeterminate
SaProt	LLR -10.41	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.021	GERP 1.7, phastCons 0.003
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 0.00048 · regional, not allelic
Overall
CADD	17.61	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R274W vs ClinVar R269W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.021% African / African-American · 12/57,160 alleles

Filtering AF 0.0121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00949%

Overall 0.00298% 36/1,207,868 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.021%	4,763
Remaining individualsnot grpmax-eligible	0.00841%	11,891
Admixed American	0.00655%	15,260
East Asian	0.00296%	33,738
South Asian	0.00176%	56,768
European (non-Finnish)	0.00168%	59,655

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: STS
Protein: p.Arg269Trp
Coding: c.805C>T
MANE Select: NM_001320752
dbSNP: rs146117456
Type: single nucleotide variant
Location: chrX:7259771 (GRCh38)
Structure: AlphaFold pLDDT 94.31 · 2 PDB
Residue 269: an α-helix

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

Similar variants

STS p.Arg269Gln Uncertain significance ★ ⚠ same residue
STS p.Gly354Arg Likely pathogenic ★★ same type
STS p.Arg381Ser Uncertain significance ★★ ⚠ same type
STS p.Asp397Asn Uncertain significance ★★ ⚠ same type
STS c.1082-55C>T Likely benign ★★ same type
STS c.1082-76G>A Benign ★★ same type
STS c.1241+15G>C Benign ★★ same type
STS c.138-9T>G Likely benign ★★ same type

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/sts-p-arg269trp (accessed [today's date]).

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