Is APAF1 p.Ile1038Val (c.3112A>G) pathogenic?

APAF1 p.Ile1038Val (c.3112A>G) is classified Benign in APAF1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-09-24). AlphaMissense: likely benign (0.0646); Rare (popmax 0.606%, amr); Associated with APAF1-related disorder.

What condition is associated with APAF1 p.Ile1038Val (c.3112A>G)?

APAF1 p.Ile1038Val (c.3112A>G) is associated with APAF1-related disorder (ClinVar).

How common is APAF1 p.Ile1038Val (c.3112A>G) in the general population?

APAF1 p.Ile1038Val (c.3112A>G) is rare (popmax 0.606%, amr) (gnomAD).

What do computational predictors say about APAF1 p.Ile1038Val (c.3112A>G)?

AlphaMissense predicts likely benign (score 0.0646) — an in-silico prediction, not a clinical call.

APAF1 p.Ile1038Val

c.3112A>G · rs146238655 · VCV3060045

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0646 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.606%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

APAF1-related disorder

Computational evidence

Protein change
AlphaMissense	0.0646	likely benign
REVEL	0.017	moderately benign-leaning
SaProt	LLR -5.83	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 0.34	GERP -4.2, phastCons 0.92
Regional constraint	o/e 0.87	unconstrained · MANE · 84 kb · p 8.3e-07 · regional, not allelic
Overall
CADD	0.019	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 0.606% Admixed American · 364/60,024 alleles

Filtering AF 0.555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.535%

Overall 0.0251% 405/1,613,674 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.606%	165
African / African-American	0.0413%	2,421
Remaining individualsnot grpmax-eligible	0.008%	12,496
European (non-Finnish)	0.000424%	235,930

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.Ile1038Val
Coding: c.3112A>G
MANE Select: NM_181861
dbSNP: rs146238655
Type: single nucleotide variant
Location: chr12:98723220 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 14 PDB

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

Disease context

APAF1-related disorder

Similar variants

APAF1 c.3457-7T>C Likely benign same condition
APAF1 c.527-10C>T Likely benign same condition
APAF1 c.956-4A>T Likely benign same condition
APAF1 c.*3T>C Benign same condition
APAF1 p.Ala304= Likely benign same condition
APAF1 p.Ala984= Benign same condition
APAF1 p.Gln416= Likely benign same condition
APAF1 p.Ile821= 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/apaf1-p-ile1038val (accessed [today's date]).

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