Is CASP9 p.Met157Val (c.469A>G) pathogenic?

CASP9 p.Met157Val (c.469A>G) is classified Likely benign in CASP9 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-12-13). AlphaMissense: likely benign (0.0738); Rare (popmax 0.157%, nfe); Associated with CASP9-related disorder.

What condition is associated with CASP9 p.Met157Val (c.469A>G)?

CASP9 p.Met157Val (c.469A>G) is associated with CASP9-related disorder (ClinVar).

How common is CASP9 p.Met157Val (c.469A>G) in the general population?

CASP9 p.Met157Val (c.469A>G) is rare (popmax 0.157%, nfe) (gnomAD).

What do computational predictors say about CASP9 p.Met157Val (c.469A>G)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

CASP9 p.Met157Val

c.469A>G · rs145118493 · VCV3034388

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.157%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CASP9-related disorder

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -5.75	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 0.15	GERP -3.4, phastCons 0.003
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	9.315	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 0.157% European (non-Finnish) · 1,857/1,180,016 alleles

Filtering AF 0.151% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.149%

Overall 0.128% 2,060/1,614,182 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.157%	635
Admixed American	0.157%	638
Remaining individualsnot grpmax-eligible	0.0992%	1,008
African / African-American	0.0333%	3,003
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,229
Finnishnot grpmax-eligible	0.0125%	8,004
South Asian	0.00769%	13,012

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.Met157Val
Coding: c.469A>G
MANE Select: NM_001229
dbSNP: rs145118493
Type: single nucleotide variant
Location: chr1:15507060 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.86 · 13 PDB
Residue 157: a β-strand

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

Disease context

CASP9-related disorder

Similar variants

CASP9 c.453+8T>C Benign same condition
CASP9 c.721-5T>C Benign same condition
CASP9 p.Ala220= Likely benign same condition
CASP9 p.Gln221Arg Benign same condition
CASP9 p.Gln44Glu Benign ⚠ same condition
CASP9 p.Leu384= Likely benign same condition
CASP9 p.Leu8= Benign same condition
CASP9 p.Phe136= Benign same condition

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-met157val (accessed [today's date]).

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