Is STS p.Pro249Leu (c.746C>T) pathogenic?

STS p.Pro249Leu (c.746C>T) is classified Uncertain significance in STS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-26). AlphaMissense: likely pathogenic (0.7611); Absent from gnomAD v4.1.

How common is STS p.Pro249Leu (c.746C>T) in the general population?

STS p.Pro249Leu (c.746C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about STS p.Pro249Leu (c.746C>T)?

AlphaMissense predicts likely pathogenic (score 0.7611) — an in-silico prediction, not a clinical call.

STS p.Pro249Leu

c.746C>T · rs2518624303 · VCV2841149

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7611 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7611	likely pathogenic
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -12.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6	GERP 6.6, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 0.00048 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P254L vs ClinVar P249L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: STS
Protein: p.Pro249Leu
Coding: c.746C>T
MANE Select: NM_001320752
dbSNP: rs2518624303
Type: single nucleotide variant
Location: chrX:7259712 (GRCh38)
Structure: AlphaFold pLDDT 94.31 · 2 PDB
Residue 254 UniProt numbering: a β-strand

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

Similar variants

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
STS c.383-16C>T Benign/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-pro249leu (accessed [today's date]).

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