Is ACP2 p.Arg356His (c.1067G>A) pathogenic?

ACP2 p.Arg356His (c.1067G>A) is classified Likely benign in ACP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-29). AlphaMissense: likely benign (0.0662); Ultra-rare (popmax 0.0329%, mid).

How common is ACP2 p.Arg356His (c.1067G>A) in the general population?

ACP2 p.Arg356His (c.1067G>A) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about ACP2 p.Arg356His (c.1067G>A)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

ACP2 p.Arg356His

c.1067G>A · rs372169625 · VCV2280857

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.024	moderately benign-leaning
SaProt	LLR -8.76	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP -3.1	GERP -4.3
Regional constraint	o/e 0.87	unconstrained · MANE · 8,670 bp · p 0.0021 · regional, not allelic
Overall
CADD	15.31	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 0.0329% Middle Eastern · 2/6,080 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00297% 48/1,614,012 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,040
South Asian	0.00878%	11,385
East Asian	0.00668%	14,960
African / African-American	0.00667%	14,987
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,004
European (non-Finnish)	0.00212%	47,200

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: ACP2
Protein: p.Arg356His
Coding: c.1067G>A
MANE Select: NM_001610
dbSNP: rs372169625
Type: single nucleotide variant
Location: chr11:47242794 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.09
Residue 356: a disulfide bond

Full ACP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACP2 p.Arg356Cys Uncertain significance ★ ⚠ same residue
ACP2 c.856-4G>A Benign ★★ same type
ACP2 p.Arg10Trp Likely benign ★★ same type
ACP2 p.Phe393Leu Benign/Likely benign ★★ same type
ACP2 p.Val416= Benign ★★ same type
ACP2 p.Ala11Glu Uncertain significance ★ ⚠ same type
ACP2 p.Ala272Val Uncertain significance ★ ⚠ same type
ACP2 p.Ala336Thr 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/acp2-p-arg356his (accessed [today's date]).

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