Is ACP4 p.Arg76His (c.227G>A) pathogenic?

ACP4 p.Arg76His (c.227G>A) is classified Uncertain significance in ACP4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.0685); Ultra-rare (popmax 0.0725%, afr).

How common is ACP4 p.Arg76His (c.227G>A) in the general population?

ACP4 p.Arg76His (c.227G>A) is ultra-rare (popmax 0.0725%, afr) (gnomAD).

What do computational predictors say about ACP4 p.Arg76His (c.227G>A)?

AlphaMissense predicts likely benign (score 0.0685) — an in-silico prediction, not a clinical call.

ACP4 p.Arg76His

c.227G>A · rs201486558 · VCV2568664

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0725%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0685	likely benign
REVEL	0.031	moderately benign-leaning
SaProt	LLR -9.57	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 0.86	GERP -3.7, phastCons 0.24
Regional constraint	o/e 1.03	unconstrained · MANE · 4,740 bp · p 0.54 · regional, not allelic
Overall
CADD	14.02	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 0.0725% African / African-American · 53/73,080 alleles

Filtering AF 0.0569% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0514%

Overall 0.00446% 69/1,547,870 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0725%	1,379
Remaining individualsnot grpmax-eligible	0.00835%	11,978
South Asian	0.00715%	13,984
Admixed American	0.00196%	50,960
European (non-Finnish)	0.000349%	286,655

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: ACP4
Protein: p.Arg76His
Coding: c.227G>A
MANE Select: NM_033068
dbSNP: rs201486558
Type: single nucleotide variant
Location: chr19:50790784 (GRCh38)
Gene constraint: LOEUF 1.413 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 88.30
Residue 76: a UniProt-annotated variant site (in ai1j and)

Full ACP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACP4 p.Arg76Cys Pathogenic ⚠ same residue
ACP4 p.Arg76fs Likely pathogenic ★ same residue
ACP4 p.Arg111Cys Pathogenic/Likely pathogenic ★★ same type
ACP4 c.550-4C>T Benign ★★ same type
ACP4 c.550-9C>T Benign ★★ same type
ACP4 p.Gly328Ala Benign ★★ same type
ACP4 p.Pro125= Benign ★★ same type
ACP4 c.645+1G>A Likely pathogenic ★ 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/acp4-p-arg76his (accessed [today's date]).

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