Is CST2 p.Gln121Glu (c.361C>G) pathogenic?

CST2 p.Gln121Glu (c.361C>G) is classified Uncertain significance in CST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.0782); Ultra-rare (popmax 0.0264%, sas).

How common is CST2 p.Gln121Glu (c.361C>G) in the general population?

CST2 p.Gln121Glu (c.361C>G) is ultra-rare (popmax 0.0264%, sas) (gnomAD).

What do computational predictors say about CST2 p.Gln121Glu (c.361C>G)?

AlphaMissense predicts likely benign (score 0.0782) — an in-silico prediction, not a clinical call.

CST2 p.Gln121Glu

c.361C>G · rs200469888 · VCV2348342

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0782 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0264%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0782	likely benign
REVEL	0.058	moderately benign-leaning
SaProt	LLR -7.54	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 -7	GERP -2.7
Regional constraint	o/e 1.40	unconstrained · MANE · 2,637 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	0.133	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 0.0264% South Asian · 24/91,070 alleles

Filtering AF 0.0181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0154%

Overall 0.00849% 137/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0264%	3,795
East Asian	0.0134%	7,478
Admixed American	0.0133%	7,501
Remaining individualsnot grpmax-eligible	0.0096%	10,417
African / African-American	0.008%	12,500
European (non-Finnish)	0.00729%	13,720
Finnishnot grpmax-eligible	0.00156%	64,046

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.Gln121Glu
Coding: c.361C>G
MANE Select: NM_001322
dbSNP: rs200469888
Type: single nucleotide variant
Location: chr20:23824085 (GRCh38)
Gene constraint: LOEUF 1.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.89
Residue 121: a disulfide bond

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

Similar variants

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
CST2 p.Arg46His 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-gln121glu (accessed [today's date]).

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