Is CASP9 p.Ala220= (c.660G>A) pathogenic?

CASP9 p.Ala220= (c.660G>A) is classified Likely benign in CASP9 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-12). Very rare (popmax 0.00833%, amr); Associated with CASP9-related disorder.

What condition is associated with CASP9 p.Ala220= (c.660G>A)?

CASP9 p.Ala220= (c.660G>A) is associated with CASP9-related disorder (ClinVar).

How common is CASP9 p.Ala220= (c.660G>A) in the general population?

CASP9 p.Ala220= (c.660G>A) is very rare (popmax 0.00833%, amr) (gnomAD).

CASP9 p.Ala220=

c.660G>A · rs943374575 · VCV3048458

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00833%, amr)

Conditions

CASP9-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.104	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -20	GERP -4.9
Overall
CADD	0.188	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00833% Admixed American · 5/60,006 alleles

Filtering AF 0.00323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00229% 37/1,613,914 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00833%	12,001
African / African-American	0.00401%	24,965
Remaining individualsnot grpmax-eligible	0.0032%	31,239
European (non-Finnish)	0.00229%	43,702

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.Ala220=
Coding: c.660G>A
MANE Select: NM_001229
dbSNP: rs943374575
Type: single nucleotide variant
Location: chr1:15506050 (GRCh38)
Gene constraint: LOEUF 0.994 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.86 · 13 PDB
Residue 220: an α-helix

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

Disease context

CASP9-related disorder

Similar variants

CASP9 p.Ala220Val Uncertain significance ★ ⚠ same residue
CASP9 c.453+8T>C Benign same condition
CASP9 c.721-5T>C 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-ala220 (accessed [today's date]).

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