Is ACAP2 p.Glu658Gly (c.1973A>G) pathogenic?

ACAP2 p.Glu658Gly (c.1973A>G) is classified Uncertain significance in ACAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-26). AlphaMissense: likely pathogenic (0.9751); Very rare (popmax 0.00134%, afr).

How common is ACAP2 p.Glu658Gly (c.1973A>G) in the general population?

ACAP2 p.Glu658Gly (c.1973A>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ACAP2 p.Glu658Gly (c.1973A>G)?

AlphaMissense predicts likely pathogenic (score 0.9751) — an in-silico prediction, not a clinical call.

ACAP2 p.Glu658Gly

c.1973A>G · rs777709903 · VCV2520329

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9751 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9751	likely pathogenic
REVEL	0.733	pathogenic-leaning
SaProt	LLR -12.96	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.64 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 13 kb · p 3.4e-07 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00134% African / African-American · 1/74,838 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000744% 12/1,613,212 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,838
European (non-Finnish)	0.000932%	107,248

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.Glu658Gly
Coding: c.1973A>G
MANE Select: NM_012287
dbSNP: rs777709903
Type: single nucleotide variant
Location: chr3:195291796 (GRCh38)
Gene constraint: LOEUF 0.47 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.71 · 1 PDB
Residue 658: an α-helix

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.Arg226Gln 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

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-glu658gly (accessed [today's date]).

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