Is ATPAF2 p.Pro43Ser (c.127C>T) pathogenic?

ATPAF2 p.Pro43Ser (c.127C>T) is classified Uncertain significance in ATPAF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-14). AlphaMissense: likely benign (0.1121); Ultra-rare (popmax 0.0117%, amr).

How common is ATPAF2 p.Pro43Ser (c.127C>T) in the general population?

ATPAF2 p.Pro43Ser (c.127C>T) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about ATPAF2 p.Pro43Ser (c.127C>T)?

AlphaMissense predicts likely benign (score 0.1121) — an in-silico prediction, not a clinical call.

ATPAF2 p.Pro43Ser

c.127C>T · VCV4750680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1121 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1121	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -6.05	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 11	GERP 1.8, phastCons 1
Regional constraint	o/e 0.58	unconstrained · MANE · 12 kb · p 5.5e-05 · regional, not allelic
Overall
CADD	22.8	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 0.0117% Admixed American · 7/60,026 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.000547% 8/1,461,670 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,575
European (non-Finnish)	8.48e-05%	1,179,866

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: ATPAF2
Protein: p.Pro43Ser
Coding: c.127C>T
MANE Select: NM_145691
Type: single nucleotide variant
Location: chr17:18038887 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 86.07

Full ATPAF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ATPAF2 p.Pro43Leu Uncertain significance ★ ⚠ same residue
ATPAF2 c.-90C>A Uncertain significance ★★ same type
ATPAF2 c.*132C>T Uncertain significance ★★ same type
ATPAF2 p.Ala130Glu Uncertain significance ★★ ⚠ same type
ATPAF2 p.Ala267Thr Uncertain significance ★★ ⚠ same type
ATPAF2 p.Ala268Thr Uncertain significance ★★ ⚠ same type
ATPAF2 p.Arg14Gly Uncertain significance ★★ ⚠ same type
ATPAF2 p.Arg189Gln 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/atpaf2-p-pro43ser (accessed [today's date]).

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