Is CST2 p.Ala2Val (c.5C>T) pathogenic?

CST2 p.Ala2Val (c.5C>T) is classified Uncertain significance in CST2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-09). AlphaMissense: likely benign (0.2023); Very rare (popmax 0.00899%, eas).

How common is CST2 p.Ala2Val (c.5C>T) in the general population?

CST2 p.Ala2Val (c.5C>T) is very rare (popmax 0.00899%, eas) (gnomAD).

What do computational predictors say about CST2 p.Ala2Val (c.5C>T)?

AlphaMissense predicts likely benign (score 0.2023) — an in-silico prediction, not a clinical call.

CST2 p.Ala2Val

c.5C>T · rs757894058 · VCV2248883

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2023 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00899%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2023	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -8.28	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 1.6	GERP 0.16, phastCons 0.22
Regional constraint	o/e 1.40	unconstrained · MANE · 2,637 bp · p 1.3e-07 · regional, not allelic
Overall
CADD	16.21	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 0.00899% East Asian · 4/44,512 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00181%

Overall 0.000749% 12/1,601,226 alleles · very rare exomes 11/1,449,046 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00899%	11,128
Remaining individualsnot grpmax-eligible	0.00484%	20,661
European (non-Finnish)	0.000426%	234,916

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.Ala2Val
Coding: c.5C>T
MANE Select: NM_001322
dbSNP: rs757894058
Type: single nucleotide variant
Location: chr20:23826656 (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.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
CST2 p.Arg72Gln 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-ala2val (accessed [today's date]).

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