Is ACP2 p.Arg254Gln (c.761G>A) pathogenic?

ACP2 p.Arg254Gln (c.761G>A) is classified Uncertain significance in ACP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-01). AlphaMissense: likely benign (0.2075); Very rare (popmax 0.00224%, eas).

How common is ACP2 p.Arg254Gln (c.761G>A) in the general population?

ACP2 p.Arg254Gln (c.761G>A) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about ACP2 p.Arg254Gln (c.761G>A)?

AlphaMissense predicts likely benign (score 0.2075) — an in-silico prediction, not a clinical call.

ACP2 p.Arg254Gln

c.761G>A · VCV4217684

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2075 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2075	likely benign
REVEL	0.444	indeterminate
SaProt	LLR -9.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 8,670 bp · p 0.0021 · regional, not allelic
Overall
CADD	32.0	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 0.00224% East Asian · 1/44,726 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000412% 6/1,455,276 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00224%	44,726
Admixed American	0.00168%	59,604
African / African-American	0.00133%	74,958
European (non-Finnish)	0.000255%	391,896

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.Arg254Gln
Coding: c.761G>A
MANE Select: NM_001610
Type: single nucleotide variant
Location: chr11:47244746 (GRCh38)
Gene constraint: LOEUF 0.804 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.09
Residue 254: a disulfide bond

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

Similar variants

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
ACP2 p.Ala336Val 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-arg254gln (accessed [today's date]).

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