Is ACAP2 p.Lys373Arg (c.1118A>G) pathogenic?

ACAP2 p.Lys373Arg (c.1118A>G) is classified Uncertain significance in ACAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely benign (0.0763); Very rare (popmax 0.00508%, amr).

How common is ACAP2 p.Lys373Arg (c.1118A>G) in the general population?

ACAP2 p.Lys373Arg (c.1118A>G) is very rare (popmax 0.00508%, amr) (gnomAD).

What do computational predictors say about ACAP2 p.Lys373Arg (c.1118A>G)?

AlphaMissense predicts likely benign (score 0.0763) — an in-silico prediction, not a clinical call.

ACAP2 p.Lys373Arg

c.1118A>G · VCV3471409

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0763 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00508%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0763	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.52	acceptor loss, 2 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.9	GERP 1.3, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 147 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	24.5	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 0.00508% Admixed American · 3/59,074 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000674%

Overall 0.000373% 6/1,608,590 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00508%	19,691
South Asian	0.00333%	30,042

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.Lys373Arg
Coding: c.1118A>G
MANE Select: NM_012287
Type: single nucleotide variant
Location: chr3:195302173 (GRCh38)
Gene constraint: LOEUF 0.47 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.71 · 1 PDB
Residue 373: the 'disordered' region

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-lys373arg (accessed [today's date]).

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