Is CST2 p.Met131Arg (c.392T>G) pathogenic?

CST2 p.Met131Arg (c.392T>G) is classified Uncertain significance in CST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: likely benign (0.1267); Ultra-rare (popmax 0.033%, mid).

How common is CST2 p.Met131Arg (c.392T>G) in the general population?

CST2 p.Met131Arg (c.392T>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CST2 p.Met131Arg (c.392T>G)?

AlphaMissense predicts likely benign (score 0.1267) — an in-silico prediction, not a clinical call.

CST2 p.Met131Arg

c.392T>G · rs202150666 · VCV2383234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1267 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1267	likely benign
REVEL	0.042	moderately benign-leaning
SaProt	LLR -8.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.8	GERP -2.7
Regional constraint	o/e 1.40	unconstrained · MANE · 2,637 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	0.109	PHRED · no single calibrated threshold — expert panels disagree

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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00995%

Overall 0.0107% 173/1,614,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
African / African-American	0.0133%	7,505
Remaining individualsnot grpmax-eligible	0.0128%	7,813
European (non-Finnish)	0.0122%	8,194
Admixed American	0.01%	10,004
South Asian	0.00329%	30,360

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: CST2
Protein: p.Met131Arg
Coding: c.392T>G
MANE Select: NM_001322
dbSNP: rs202150666
Type: single nucleotide variant
Location: chr20:23824054 (GRCh38)
Gene constraint: LOEUF 1.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.89
Residue 131: a disulfide bond

Full CST2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST2 p.Met131Ile Uncertain significance ★ ⚠ same residue
CST2 p.Arg69Trp Benign ★★ ⚠ same type
CST2 p.Ala16Val Uncertain significance ★ ⚠ same type
CST2 p.Ala2Val Uncertain significance ★ ⚠ same type
CST2 p.Ala58Val Uncertain significance ★ ⚠ same type
CST2 p.Ala73Val Uncertain significance ★ ⚠ same type
CST2 p.Arg130Gly Uncertain significance ★ ⚠ same type
CST2 p.Arg28Lys Uncertain significance ★ ⚠ 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/cst2-p-met131arg (accessed [today's date]).

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