Is APAF1 p.Pro571Leu (c.1712C>T) pathogenic?

APAF1 p.Pro571Leu (c.1712C>T) is classified Uncertain significance in APAF1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-04-07). AlphaMissense: likely benign (0.1536); Ultra-rare (popmax 0.0178%, eas).

How common is APAF1 p.Pro571Leu (c.1712C>T) in the general population?

APAF1 p.Pro571Leu (c.1712C>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about APAF1 p.Pro571Leu (c.1712C>T)?

AlphaMissense predicts likely benign (score 0.1536) — an in-silico prediction, not a clinical call.

APAF1 p.Pro571Leu

c.1712C>T · rs752612461 · VCV2517932

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1536 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1536	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -8.60	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 3.2	GERP 1.3, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 84 kb · p 8.3e-07 · regional, not allelic
Overall
CADD	23.3	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 0.0178% East Asian · 8/44,864 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.0026% 42/1,613,694 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,608
African / African-American	0.00401%	24,935
European (non-Finnish)	0.00246%	40,689
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,054

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.Pro571Leu
Coding: c.1712C>T
MANE Select: NM_181861
dbSNP: rs752612461
Type: single nucleotide variant
Location: chr12:98671638 (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

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-pro571leu (accessed [today's date]).

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