Is CASP9 p.Leu142Phe (c.424C>T) pathogenic?

CASP9 p.Leu142Phe (c.424C>T) is classified Uncertain significance in CASP9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-26). AlphaMissense: likely benign (0.0841); Ultra-rare (popmax 0.0147%, afr).

How common is CASP9 p.Leu142Phe (c.424C>T) in the general population?

CASP9 p.Leu142Phe (c.424C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about CASP9 p.Leu142Phe (c.424C>T)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

CASP9 p.Leu142Phe

c.424C>T · VCV3485279

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -8.34	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 3.1	GERP 0.8, phastCons 0.87
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	10.14	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 0.0147% African / African-American · 11/74,934 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000805% 13/1,614,010 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,812
Remaining individualsnot grpmax-eligible	0.0032%	31,242

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.Leu142Phe
Coding: c.424C>T
MANE Select: NM_001229
Type: single nucleotide variant
Location: chr1:15507902 (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 p.Leu142Pro Likely benign ★ same residue
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

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-leu142phe (accessed [today's date]).

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