Is CASP9 p.Met39Ile (c.117G>T) pathogenic?

CASP9 p.Met39Ile (c.117G>T) is classified Uncertain significance in CASP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-25). AlphaMissense: likely pathogenic (0.8134); Very rare (popmax 0.00205%, amr).

How common is CASP9 p.Met39Ile (c.117G>T) in the general population?

CASP9 p.Met39Ile (c.117G>T) is very rare (popmax 0.00205%, amr) (gnomAD).

What do computational predictors say about CASP9 p.Met39Ile (c.117G>T)?

AlphaMissense predicts likely pathogenic (score 0.8134) — an in-silico prediction, not a clinical call.

CASP9 p.Met39Ile

c.117G>T · rs759277328 · VCV2540333

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8134 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00205%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8134	likely pathogenic
REVEL	0.234	benign-leaning
SaProt	LLR -8.00	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.3, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	28.2	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 0.00205% Admixed American · 1/48,832 alleles

Filtering AF 8.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.6e-05%

Overall 0.000395% 6/1,520,282 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00205%	48,832
Remaining individualsnot grpmax-eligible	0.0017%	58,920
European (non-Finnish)	0.000351%	284,539

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.Met39Ile
Coding: c.117G>T
MANE Select: NM_001229
dbSNP: rs759277328
Type: single nucleotide variant
Location: chr1:15524084 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.86 · 13 PDB
Residue 39: an α-helix; the card domain

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-met39ile (accessed [today's date]).

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