Is APAF1 p.Ala223Ser (c.667G>T) pathogenic?

APAF1 p.Ala223Ser (c.667G>T) is classified Uncertain significance in APAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-01). AlphaMissense: likely benign (0.2819); Very rare (popmax 0.00398%, nfe).

How common is APAF1 p.Ala223Ser (c.667G>T) in the general population?

APAF1 p.Ala223Ser (c.667G>T) is very rare (popmax 0.00398%, nfe) (gnomAD).

What do computational predictors say about APAF1 p.Ala223Ser (c.667G>T)?

AlphaMissense predicts likely benign (score 0.2819) — an in-silico prediction, not a clinical call.

APAF1 p.Ala223Ser

c.667G>T · VCV4116880

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2819 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2819	likely benign
REVEL	0.649	pathogenic-leaning
SaProt	LLR -10.42	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 84 kb · p 8.3e-07 · regional, not allelic
Overall
CADD	26.5	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 0.00398% European (non-Finnish) · 47/1,180,046 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.00304% 49/1,614,084 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00398%	25,107
Admixed American	0.00167%	60,002
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: APAF1
Protein: p.Ala223Ser
Coding: c.667G>T
MANE Select: NM_181861
Type: single nucleotide variant
Location: chr12:98659300 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 14 PDB
Residue 223: the nb-arc domain; an α-helix

Full APAF1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APAF1 c.2047-3T>C Benign ★★ same type
APAF1 p.Glu625Ala Benign ★★ same type
APAF1 p.Ser871Leu Likely benign ★★ ⚠ same type
APAF1 p.Thr446Ser Benign ★★ same type
APAF1 p.Tyr359= Benign ★★ same type
APAF1 p.Ala1025Val Uncertain significance ★ ⚠ same type
APAF1 p.Ala304Thr Uncertain significance ★ ⚠ same type
APAF1 p.Ala584Asp 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/apaf1-p-ala223ser (accessed [today's date]).

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