Is STS p.Pro274Leu (c.821C>T) pathogenic?

STS p.Pro274Leu (c.821C>T) is classified Uncertain significance in STS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: ambiguous (0.3885); Ultra-rare (popmax 0.0486%, mid); Associated with Inborn genetic diseases.

What condition is associated with STS p.Pro274Leu (c.821C>T)?

STS p.Pro274Leu (c.821C>T) is associated with Inborn genetic diseases (ClinVar).

How common is STS p.Pro274Leu (c.821C>T) in the general population?

STS p.Pro274Leu (c.821C>T) is ultra-rare (popmax 0.0486%, mid) (gnomAD).

What do computational predictors say about STS p.Pro274Leu (c.821C>T)?

AlphaMissense predicts ambiguous (score 0.3885) — an in-silico prediction, not a clinical call.

STS p.Pro274Leu

c.821C>T · VCV4177199

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3885 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0486%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3885	ambiguous
REVEL	0.692	pathogenic-leaning
SaProt	LLR -9.75	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 5.7, phastCons 0.99
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 0.00048 · regional, not allelic
Overall
CADD	20.5	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 P279L vs ClinVar P274L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0486% Middle Eastern · 2/4,115 alleles

Filtering AF 0.00856% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00646%

Overall 0.00731% 86/1,175,918 alleles · ultra-rare exomes 81/1,076,172 · genomes 5/99,746 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0486%	2,057
European (non-Finnish)	0.00864%	11,567
South Asian	0.00559%	17,887
Remaining individualsnot grpmax-eligible	0.0043%	23,240
African / African-American	0.00378%	26,474
East Asian	0.00306%	32,662

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.Pro274Leu
Coding: c.821C>T
MANE Select: NM_001320752
Type: single nucleotide variant
Location: chrX:7275965 (GRCh38)
Structure: AlphaFold pLDDT 94.31 · 2 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

STS p.Pro274= Likely benign ★ same residue
STS p.Arg381Ser Uncertain significance ★★ ⚠ same condition
STS p.Asp397Asn Uncertain significance ★★ ⚠ same condition
STS p.Arg578His Benign/Likely benign ★★ same condition
STS c.943+5G>A Conflicting classifications of pathogenicity ★ same condition
STS p.Ala295Val Uncertain significance ★ ⚠ same condition
STS p.Ala529Val Uncertain significance ★ ⚠ same condition
STS p.Arg179Ser 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/sts-p-pro274leu (accessed [today's date]).

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