Is CST2 p.Glu124Lys (c.370G>A) pathogenic?

CST2 p.Glu124Lys (c.370G>A) is classified Uncertain significance in CST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-07). AlphaMissense: likely benign (0.3042); Ultra-rare (popmax 0.0156%, eas).

How common is CST2 p.Glu124Lys (c.370G>A) in the general population?

CST2 p.Glu124Lys (c.370G>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about CST2 p.Glu124Lys (c.370G>A)?

AlphaMissense predicts likely benign (score 0.3042) — an in-silico prediction, not a clinical call.

CST2 p.Glu124Lys

c.370G>A · rs372139444 · VCV2519438

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3042 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3042	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.34	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -4.7	GERP -1.2
Regional constraint	o/e 1.40	unconstrained · MANE · 2,637 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	6.166	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 0.0156% East Asian · 7/44,874 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00652%

Overall 0.0106% 171/1,613,884 alleles · ultra-rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0765%	1,307
East Asiangrpmax	0.0156%	6,411
Remaining individualsnot grpmax-eligible	0.0128%	7,810
African / African-American	0.00935%	10,697
European (non-Finnish)	0.00839%	11,919
Admixed American	0.00167%	59,996

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu124Lys
Coding: c.370G>A
MANE Select: NM_001322
dbSNP: rs372139444
Type: single nucleotide variant
Location: chr20:23824076 (GRCh38)
Gene constraint: LOEUF 1.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.89
Residue 124: 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-glu124lys (accessed [today's date]).

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