Is APAF1 p.Arg337Cys (c.1009C>T) pathogenic?

APAF1 p.Arg337Cys (c.1009C>T) is classified Uncertain significance in APAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-16). AlphaMissense: likely pathogenic (0.6316); Very rare (popmax 0.0011%, sas).

How common is APAF1 p.Arg337Cys (c.1009C>T) in the general population?

APAF1 p.Arg337Cys (c.1009C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about APAF1 p.Arg337Cys (c.1009C>T)?

AlphaMissense predicts likely pathogenic (score 0.6316) — an in-silico prediction, not a clinical call.

APAF1 p.Arg337Cys

c.1009C>T · rs773574010 · VCV3127602

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6316	likely pathogenic
REVEL	0.845	moderately pathogenic-leaning
SaProt	LLR -12.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.99 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 84 kb · p 8.3e-07 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/91,060 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000342% 5/1,461,748 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00157%	63,888
South Asiangrpmax	0.0011%	91,060
European (non-Finnish)	0.000254%	393,306

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg337Cys
Coding: c.1009C>T
MANE Select: NM_181861
dbSNP: rs773574010
Type: single nucleotide variant
Location: chr12:98665606 (GRCh38)
Gene constraint: LOEUF 0.664 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 14 PDB
Residue 337: the nb-arc domain

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-arg337cys (accessed [today's date]).

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