Is STS p.Pro22Leu (c.65C>T) pathogenic?

STS p.Pro22Leu (c.65C>T) is classified Uncertain significance in STS (ClinVar, Single submitter, 1 submitter; last evaluated 2020-10-12). AlphaMissense: ambiguous (0.4983); Very rare (popmax 0.00351%, afr).

How common is STS p.Pro22Leu (c.65C>T) in the general population?

STS p.Pro22Leu (c.65C>T) is very rare (popmax 0.00351%, afr) (gnomAD).

What do computational predictors say about STS p.Pro22Leu (c.65C>T)?

AlphaMissense predicts ambiguous (score 0.4983) — an in-silico prediction, not a clinical call.

STS p.Pro22Leu

c.65C>T · rs1233947671 · VCV1315048

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00351%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4983	ambiguous
REVEL	0.804	moderately pathogenic-leaning
SaProt	LLR -13.38	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 6.6, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 0.00048 · regional, not allelic
Overall
CADD	21.6	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 P27L vs ClinVar P22L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00351% African / African-American · 2/57,043 alleles

Filtering AF 0.00238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00206%

Overall 0.00281% 34/1,209,464 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00351%	28,521
European (non-Finnish)	0.00335%	29,833
Remaining individualsnot grpmax-eligible	0.0021%	47,577
South Asian	0.00176%	56,777

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.Pro22Leu
Coding: c.65C>T
MANE Select: NM_001320752
dbSNP: rs1233947671
Type: single nucleotide variant
Location: chrX:7253264 (GRCh38)
Structure: AlphaFold pLDDT 94.31 · 2 PDB

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-pro22leu (accessed [today's date]).

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