Is CST3 p.Thr97Ile (c.290C>T) pathogenic?

CST3 p.Thr97Ile (c.290C>T) is classified Uncertain significance in CST3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-17). AlphaMissense: likely pathogenic (0.9957); Very rare (popmax 0.00432%, nfe).

How common is CST3 p.Thr97Ile (c.290C>T) in the general population?

CST3 p.Thr97Ile (c.290C>T) is very rare (popmax 0.00432%, nfe) (gnomAD).

What do computational predictors say about CST3 p.Thr97Ile (c.290C>T)?

AlphaMissense predicts likely pathogenic (score 0.9957) — an in-silico prediction, not a clinical call.

CST3 p.Thr97Ile

c.290C>T · rs1355608117 · VCV2210184

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9957 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00432%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9957	likely pathogenic · top 1% in CST3
REVEL	0.457	indeterminate
SaProt	LLR -13.38	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 3,943 bp · p 0.022 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00432% European (non-Finnish) · 51/1,179,750 alleles

Filtering AF 0.00334% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00302%

Overall 0.00349% 51/1,461,616 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.Thr97Ile
Coding: c.290C>T
MANE Select: NM_000099
dbSNP: rs1355608117
Type: single nucleotide variant
Location: chr20:23635321 (GRCh38)
Gene constraint: LOEUF 1.912 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.56 · 11 PDB
Residue 97: a β-strand

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

Similar variants

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
CST3 p.Ala25Thr Benign/Likely benign ★★ ⚠ same type
CST3 p.Ala72Ser Benign ★★ ⚠ same type
CST3 p.Arg6= Benign/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-thr97ile (accessed [today's date]).

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