Is CASP9 p.Ala331Thr (c.991G>A) pathogenic?

CASP9 p.Ala331Thr (c.991G>A) is classified Uncertain significance in CASP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-25). AlphaMissense: likely benign (0.283); Very rare (popmax 0.00404%, afr).

How common is CASP9 p.Ala331Thr (c.991G>A) in the general population?

CASP9 p.Ala331Thr (c.991G>A) is very rare (popmax 0.00404%, afr) (gnomAD).

What do computational predictors say about CASP9 p.Ala331Thr (c.991G>A)?

AlphaMissense predicts likely benign (score 0.283) — an in-silico prediction, not a clinical call.

CASP9 p.Ala331Thr

c.991G>A · VCV3827593

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.283 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00404%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.283	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -5.85	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 0.49, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	25.0	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 0.00404% African / African-American · 3/74,292 alleles

Filtering AF 0.00181% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.0023% 37/1,610,582 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00404%	24,764
Admixed American	0.00337%	29,717
European (non-Finnish)	0.00254%	39,299
South Asian	0.00221%	45,210

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: CASP9
Protein: p.Ala331Thr
Coding: c.991G>A
MANE Select: NM_001229
Type: single nucleotide variant
Location: chr1:15495330 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.86 · 13 PDB

Full CASP9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CASP9 c.720+9C>T Benign ★★ same type
CASP9 p.Ala28Val Benign ★★ same type
CASP9 p.Thr366Asn Benign ★★ same type
CASP9 p.Ala141Val Uncertain significance ★ ⚠ same type
CASP9 p.Ala215Thr Uncertain significance ★ ⚠ same type
CASP9 p.Ala220Val Uncertain significance ★ same type
CASP9 p.Ala226Ser Uncertain significance ★ ⚠ same type
CASP9 p.Ala28Thr 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/casp9-p-ala331thr (accessed [today's date]).

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