Is CST3 p.Val92Met (c.274G>A) pathogenic?

CST3 p.Val92Met (c.274G>A) is classified Uncertain significance in CST3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-02). AlphaMissense: ambiguous (0.4294); Very rare (popmax 0.00446%, eas).

How common is CST3 p.Val92Met (c.274G>A) in the general population?

CST3 p.Val92Met (c.274G>A) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CST3 p.Val92Met (c.274G>A)?

AlphaMissense predicts ambiguous (score 0.4294) — an in-silico prediction, not a clinical call.

CST3 p.Val92Met

c.274G>A · VCV4695239

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4294 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4294	ambiguous
REVEL	0.21	benign-leaning
SaProt	LLR -11.17	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 1.4, phastCons 0.99
Regional constraint	o/e 1.16	unconstrained · MANE · 3,943 bp · p 0.022 · regional, not allelic
Overall
CADD	19.84	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000992% 16/1,613,576 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,436
African / African-American	0.00134%	74,794
European (non-Finnish)	0.0011%	90,761

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: CST3
Protein: p.Val92Met
Coding: c.274G>A
MANE Select: NM_000099
Type: single nucleotide variant
Location: chr20:23635337 (GRCh38)
Gene constraint: LOEUF 1.912 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.56 · 11 PDB
Residue 92: a β-strand

Full CST3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST3 p.Arg71His Uncertain significance ★★ ⚠ same type
CST3 p.His112Arg Uncertain significance ★★ ⚠ same type
CST3 p.Met67Val Uncertain significance ★★ ⚠ same type
CST3 p.Pro8Ser Uncertain significance ★★ ⚠ same type
CST3 c.243+11C>T Likely benign ★★ same type
CST3 p.Ala25Thr Benign/Likely benign ★★ same type
CST3 p.Ala72Ser Benign ★★ ⚠ same type
CST3 p.Arg6= 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/cst3-p-val92met (accessed [today's date]).

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