Is CASP9 p.Phe136= (c.408T>C) pathogenic?

CASP9 p.Phe136= (c.408T>C) is classified Benign in CASP9 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-10-18). Common (popmax 70.5%, afr) — too common for a highly-penetrant pathogenic allele; Associated with CASP9-related disorder.

What condition is associated with CASP9 p.Phe136= (c.408T>C)?

CASP9 p.Phe136= (c.408T>C) is associated with CASP9-related disorder (ClinVar).

CASP9 p.Phe136=

Q: How common is CASP9 p.Phe136= (c.408T>C) in the general population?

CASP9 p.Phe136= (c.408T>C) is common (popmax 70.5%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.408T>C · rs1132312 · VCV3058888

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 70.5%, afr) — too common for a highly-penetrant pathogenic allele

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 1.4	GERP -4.5, phastCons 0.002
Overall
CADD	1.399	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 70.5% African / African-American · 52,823/74,968 alleles

Filtering AF 70% ClinGen BA1/BS1 input FAF95, joint · FAF99 69.7%

Overall 53.7% 866,370/1,613,430 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	70.5%	1
East Asian	64.5%	2
Finnishnot grpmax-eligible	64%	2
Remaining individualsnot grpmax-eligible	54%	2
European (non-Finnish)	53.1%	2
Amishnot grpmax-eligible	51.2%	2
Middle Eastern	51%	2
Ashkenazi Jewishnot grpmax-eligible	49.9%	2
Admixed American	43.9%	2
South Asian	43.2%	2

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.Phe136=
Coding: c.408T>C
MANE Select: NM_001229
dbSNP: rs1132312
Type: single nucleotide variant
Location: chr1:15518120 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.86 · 13 PDB
Residue 136: a UniProt-annotated variant site (in)

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.Met157Val Likely 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-phe136 (accessed [today's date]).

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