Is STS p.Pro146Ala (c.436C>G) pathogenic?

STS p.Pro146Ala (c.436C>G) is classified Uncertain significance in STS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-08). AlphaMissense: likely pathogenic (0.6321); Ultra-rare (popmax 0.0534%, eas); Associated with Inborn genetic diseases.

What condition is associated with STS p.Pro146Ala (c.436C>G)?

STS p.Pro146Ala (c.436C>G) is associated with Inborn genetic diseases (ClinVar).

How common is STS p.Pro146Ala (c.436C>G) in the general population?

STS p.Pro146Ala (c.436C>G) is ultra-rare (popmax 0.0534%, eas) (gnomAD).

What do computational predictors say about STS p.Pro146Ala (c.436C>G)?

AlphaMissense predicts likely pathogenic (score 0.6321) — an in-silico prediction, not a clinical call.

STS p.Pro146Ala

c.436C>G · rs199596711 · VCV3171687

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6321 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0534%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.6321	likely pathogenic
REVEL	0.883	moderately pathogenic-leaning
SaProt	LLR -12.09	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 6.7, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 72 kb · p 0.00048 · regional, not allelic
Overall
CADD	22.9	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 P151A vs ClinVar P146A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0534% East Asian · 18/33,725 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0284%

Overall 0.00339% 41/1,209,454 alleles · ultra-rare exomes 26/1,097,949 · genomes 15/111,505 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0534%	1,874
Admixed American	0.0438%	2,285
European (non-Finnish)	0.000335%	298,320

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.Pro146Ala
Coding: c.436C>G
MANE Select: NM_001320752
dbSNP: rs199596711
Type: single nucleotide variant
Location: chrX:7259402 (GRCh38)
Structure: AlphaFold pLDDT 94.31 · 2 PDB
Residue 151 UniProt numbering: an α-helix

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.Arg381Ser Uncertain significance ★★ ⚠ same condition
STS p.Asp397Asn Uncertain significance ★★ ⚠ same condition
STS p.Arg578His Benign/Likely benign ★★ same condition
STS p.Pro146fs Likely pathogenic ★ same residue
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-pro146ala (accessed [today's date]).

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