Is CST3 p.Ala121Val (c.362C>T) pathogenic?

CST3 p.Ala121Val (c.362C>T) is classified Uncertain significance in CST3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-29). AlphaMissense: likely benign (0.0983); Very rare (popmax 0.00668%, eas).

How common is CST3 p.Ala121Val (c.362C>T) in the general population?

CST3 p.Ala121Val (c.362C>T) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about CST3 p.Ala121Val (c.362C>T)?

AlphaMissense predicts likely benign (score 0.0983) — an in-silico prediction, not a clinical call.

CST3 p.Ala121Val

c.362C>T · rs755513850 · VCV2602746

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0983 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0983	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -5.76	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 -1.8	GERP -2.8
Regional constraint	o/e 1.16	unconstrained · MANE · 3,943 bp · p 0.022 · regional, not allelic
Overall
CADD	0.14	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 0.00668% East Asian · 3/44,888 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00031% 5/1,613,760 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,963
Remaining individualsnot grpmax-eligible	0.0032%	31,235

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: CST3
Protein: p.Ala121Val
Coding: c.362C>T
MANE Select: NM_000099
dbSNP: rs755513850
Type: single nucleotide variant
Location: chr20:23633995 (GRCh38)
Gene constraint: LOEUF 1.912 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.56 · 11 PDB
Residue 121: a β-strand; a UniProt-annotated variant site (in adldwa; likely pathogenic)

Full CST3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CST3 p.Ala121Pro Uncertain significance ★ ⚠ same residue
CST3 p.Ala121= Likely benign ★ same residue
CST3 p.Ala121fs Uncertain significance ★ same residue
CST3 p.Arg71His Uncertain significance ★★ ⚠ same type
CST3 p.His112Arg Uncertain significance ★★ ⚠ same type
CST3 p.Met67Val Uncertain significance ★★ ⚠ same type
CST3 p.Pro8Ser Uncertain significance ★★ ⚠ same type
CST3 c.243+11C>T Likely benign ★★ 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/cst3-p-ala121val (accessed [today's date]).

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