Is CST3 p.Ala121Pro (c.361G>C) pathogenic?

CST3 p.Ala121Pro (c.361G>C) is classified Uncertain significance in CST3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-29). AlphaMissense: likely pathogenic (0.8472); Very rare (popmax 6.84e-05%).

How common is CST3 p.Ala121Pro (c.361G>C) in the general population?

CST3 p.Ala121Pro (c.361G>C) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about CST3 p.Ala121Pro (c.361G>C)?

AlphaMissense predicts likely pathogenic (score 0.8472) — an in-silico prediction, not a clinical call.

CST3 p.Ala121Pro

c.361G>C · rs1394879622 · VCV1904796

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8472 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8472	likely pathogenic
REVEL	0.131	moderately benign-leaning
SaProt	LLR -11.79	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.4	GERP -2.8
Regional constraint	o/e 1.16	unconstrained · MANE · 3,943 bp · p 0.022 · regional, not allelic
Overall
CADD	9.115	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 6.84e-05%

Overall 6.84e-05% 1/1,461,598 alleles · very rare

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.Ala121Pro
Coding: c.361G>C
MANE Select: NM_000099
dbSNP: rs1394879622
Type: single nucleotide variant
Location: chr20:23633996 (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.Ala121Val 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-ala121pro (accessed [today's date]).

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