Is ACAP2 p.Arg226Gln (c.677G>A) pathogenic?

ACAP2 p.Arg226Gln (c.677G>A) is classified Uncertain significance in ACAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely benign (0.0523); Very rare (popmax 0.00401%, afr).

How common is ACAP2 p.Arg226Gln (c.677G>A) in the general population?

ACAP2 p.Arg226Gln (c.677G>A) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about ACAP2 p.Arg226Gln (c.677G>A)?

AlphaMissense predicts likely benign (score 0.0523) — an in-silico prediction, not a clinical call.

ACAP2 p.Arg226Gln

c.677G>A · rs1232089082 · VCV2490323

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0523 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0523	likely benign
REVEL	0.049	moderately benign-leaning
SaProt	LLR -3.08	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 0.55	GERP -0.23, phastCons 0.99
Regional constraint	o/e 0.66	unconstrained · MANE · 147 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	17.75	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 0.00401% African / African-American · 3/74,856 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.00031% 5/1,613,428 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,952
South Asian	0.0011%	91,030
European (non-Finnish)	8.48e-05%	1,179,800

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: ACAP2
Protein: p.Arg226Gln
Coding: c.677G>A
MANE Select: NM_012287
dbSNP: rs1232089082
Type: single nucleotide variant
Location: chr3:195326952 (GRCh38)
Gene constraint: LOEUF 0.47 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.71 · 1 PDB
Residue 226: the bar domain

Full ACAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAP2 c.53+1G>A Uncertain significance ★ same type
ACAP2 p.Arg167Gln Uncertain significance ★ ⚠ same type
ACAP2 p.Arg287His Uncertain significance ★ ⚠ same type
ACAP2 p.Arg404Gln Uncertain significance ★ ⚠ same type
ACAP2 p.Arg755His Uncertain significance ★ ⚠ same type
ACAP2 p.Asn265His Uncertain significance ★ ⚠ same type
ACAP2 p.Asn265Ser Uncertain significance ★ ⚠ same type
ACAP2 p.Asn389Lys 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/acap2-p-arg226gln (accessed [today's date]).

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