Is CASP9 p.Thr366Asn (c.1097C>A) pathogenic?

CASP9 p.Thr366Asn (c.1097C>A) is classified Benign in CASP9 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.1845); Low-frequency (popmax 2.84%, afr).

How common is CASP9 p.Thr366Asn (c.1097C>A) in the general population?

CASP9 p.Thr366Asn (c.1097C>A) is low-frequency (popmax 2.84%, afr) (gnomAD).

What do computational predictors say about CASP9 p.Thr366Asn (c.1097C>A)?

AlphaMissense predicts likely benign (score 0.1845) — an in-silico prediction, not a clinical call.

CASP9 p.Thr366Asn

c.1097C>A · rs61738967 · VCV782360

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1845 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.84%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1845	likely benign
REVEL	0.34	indeterminate
SaProt	LLR -9.28	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.7, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 31 kb · p 0.1 · regional, not allelic
Overall
CADD	23.3	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 2.84% African / African-American · 2,122/74,806 alleles

Filtering AF 2.74% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.7%

Overall 0.189% 3,028/1,604,750 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	2.84%	35
South Asian	0.262%	382
Middle Eastern	0.248%	403
Admixed American	0.243%	411
Remaining individualsnot grpmax-eligible	0.241%	414
European (non-Finnish)	0.0309%	3,238

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.Thr366Asn
Coding: c.1097C>A
MANE Select: NM_001229
dbSNP: rs61738967
Type: single nucleotide variant
Location: chr1:15493953 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.86 · 13 PDB
Residue 366: an α-helix

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.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
CASP9 p.Ala331Thr 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-thr366asn (accessed [today's date]).

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