Is APAF1 p.Arg13Gly (c.37A>G) pathogenic?

APAF1 p.Arg13Gly (c.37A>G) is classified Uncertain significance in APAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-16). AlphaMissense: likely benign (0.2282); Ultra-rare (popmax 0.066%, mid).

How common is APAF1 p.Arg13Gly (c.37A>G) in the general population?

APAF1 p.Arg13Gly (c.37A>G) is ultra-rare (popmax 0.066%, mid) (gnomAD).

What do computational predictors say about APAF1 p.Arg13Gly (c.37A>G)?

AlphaMissense predicts likely benign (score 0.2282) — an in-silico prediction, not a clinical call.

APAF1 p.Arg13Gly

c.37A>G · rs966090697 · VCV2386924

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2282 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.066%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2282	likely benign
REVEL	0.139	moderately benign-leaning
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.23, phastCons 0.99
Regional constraint	o/e 0.87	unconstrained · MANE · 84 kb · p 8.3e-07 · regional, not allelic
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.066% Middle Eastern · 4/6,058 alleles

Filtering AF 0.0225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.000479% 7/1,461,764 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.066%	1,514
Remaining individualsnot grpmax-eligible	0.0016%	62,502
European (non-Finnish)	0.000169%	589,991

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.Arg13Gly
Coding: c.37A>G
MANE Select: NM_181861
dbSNP: rs966090697
Type: single nucleotide variant
Location: chr12:98648396 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 14 PDB
Residue 13: the card 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.Ala223Ser Uncertain significance ★ ⚠ same type
APAF1 p.Ala304Thr 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-arg13gly (accessed [today's date]).

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