Is ACAP3 p.Arg427His (c.1280G>A) pathogenic?

ACAP3 p.Arg427His (c.1280G>A) is classified Uncertain significance in ACAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.1525); Ultra-rare (popmax 0.0579%, nfe).

How common is ACAP3 p.Arg427His (c.1280G>A) in the general population?

ACAP3 p.Arg427His (c.1280G>A) is ultra-rare (popmax 0.0579%, nfe) (gnomAD).

What do computational predictors say about ACAP3 p.Arg427His (c.1280G>A)?

AlphaMissense predicts likely benign (score 0.1525) — an in-silico prediction, not a clinical call.

ACAP3 p.Arg427His

c.1280G>A · rs563840123 · VCV2511730

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1525 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0579%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1525	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -10.19	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP -1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 14 kb · p 0.33 · regional, not allelic
Overall
CADD	33.0	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 0.0579% European (non-Finnish) · 664/1,147,082 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0528%

Overall 0.0467% 721/1,544,208 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0579%	1,728
Admixed American	0.047%	2,127
Remaining individualsnot grpmax-eligible	0.03%	3,335
Finnishnot grpmax-eligible	0.0229%	4,366
African / African-American	0.00274%	36,530
South Asian	0.00119%	84,066

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: ACAP3
Protein: p.Arg427His
Coding: c.1280G>A
MANE Select: NM_030649
dbSNP: rs563840123
Type: single nucleotide variant
Location: chr1:1296482 (GRCh38)
Gene constraint: LOEUF 0.816 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.31
Residue 427: the arf-gap domain

Full ACAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAP3 p.Arg427Cys Uncertain significance ★ ⚠ same residue
ACAP3 p.Arg427Gly Uncertain significance ★ ⚠ same residue
ACAP3 p.Ala242Val Uncertain significance ★ ⚠ same type
ACAP3 p.Ala265Val Uncertain significance ★ ⚠ same type
ACAP3 p.Ala282Thr Uncertain significance ★ ⚠ same type
ACAP3 p.Ala307Thr Uncertain significance ★ ⚠ same type
ACAP3 p.Ala392Thr Uncertain significance ★ ⚠ same type
ACAP3 p.Ala526Thr 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/acap3-p-arg427his (accessed [today's date]).

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