Is CASP9 p.Leu8= (c.24C>T) pathogenic?

CASP9 p.Leu8= (c.24C>T) is classified Benign in CASP9 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-25). Low-frequency (popmax 1.05%, afr); Associated with CASP9-related disorder.

What condition is associated with CASP9 p.Leu8= (c.24C>T)?

CASP9 p.Leu8= (c.24C>T) is associated with CASP9-related disorder (ClinVar).

How common is CASP9 p.Leu8= (c.24C>T) in the general population?

CASP9 p.Leu8= (c.24C>T) is low-frequency (popmax 1.05%, afr) (gnomAD).

CASP9 p.Leu8=

c.24C>T · rs370730070 · VCV3052276

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

low-frequency (popmax 1.05%, afr)

Conditions

CASP9-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.38	GERP -4.6, phastCons 0.003
Overall
CADD	2.49	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.05% African / African-American · 766/73,050 alleles

Filtering AF 0.987% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.962%

Overall 0.0555% 857/1,543,706 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.05%	95
Middle Eastern	0.0668%	1,497
Remaining individualsnot grpmax-eligible	0.0667%	1,500
Admixed American	0.0487%	2,054
South Asian	0.00237%	42,108
European (non-Finnish)	0.00183%	54,739

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.Leu8=
Coding: c.24C>T
MANE Select: NM_001229
dbSNP: rs370730070
Type: single nucleotide variant
Location: chr1:15524177 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.86 · 13 PDB
Residue 8: an α-helix; the card domain

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.Met157Val Likely 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-leu8 (accessed [today's date]).

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