Is CST2 p.Val78Met (c.232G>A) pathogenic?

CST2 p.Val78Met (c.232G>A) is classified Uncertain significance in CST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-29). AlphaMissense: ambiguous (0.3905); Ultra-rare (popmax 0.018%, mid).

How common is CST2 p.Val78Met (c.232G>A) in the general population?

CST2 p.Val78Met (c.232G>A) is ultra-rare (popmax 0.018%, mid) (gnomAD).

What do computational predictors say about CST2 p.Val78Met (c.232G>A)?

AlphaMissense predicts ambiguous (score 0.3905) — an in-silico prediction, not a clinical call.

CST2 p.Val78Met

c.232G>A · rs141816898 · VCV2600444

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3905 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.018%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3905	ambiguous
REVEL	0.173	moderately benign-leaning
SaProt	LLR -11.39	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 0.95	GERP 0.41, phastCons 0.001
Regional constraint	o/e 1.40	unconstrained · MANE · 2,637 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	21.2	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 0.018% Middle Eastern · 1/5,560 alleles

Filtering AF 0.00131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00112%

Overall 0.00179% 26/1,455,252 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.018%	5,560
Admixed American	0.00206%	48,534
European (non-Finnish)	0.00201%	49,826
African / African-American	0.00182%	54,852
Remaining individualsnot grpmax-eligible	0.00178%	56,026

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.Val78Met
Coding: c.232G>A
MANE Select: NM_001322
dbSNP: rs141816898
Type: single nucleotide variant
Location: chr20:23825320 (GRCh38)
Gene constraint: LOEUF 1.951 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.89

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-val78met (accessed [today's date]).

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