Is ACAP2 p.Met467Thr (c.1400T>C) pathogenic?

ACAP2 p.Met467Thr (c.1400T>C) is classified Uncertain significance in ACAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). AlphaMissense: likely pathogenic (0.9955); Very rare (popmax 0.00402%, afr).

How common is ACAP2 p.Met467Thr (c.1400T>C) in the general population?

ACAP2 p.Met467Thr (c.1400T>C) is very rare (popmax 0.00402%, afr) (gnomAD).

What do computational predictors say about ACAP2 p.Met467Thr (c.1400T>C)?

AlphaMissense predicts likely pathogenic (score 0.9955) — an in-silico prediction, not a clinical call.

ACAP2 p.Met467Thr

c.1400T>C · rs1161438810 · VCV2493352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9955 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00402%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9955	likely pathogenic
REVEL	0.625	indeterminate
SaProt	LLR -13.96	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.58 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 147 kb · p 1.3e-16 · regional, not allelic
Overall
CADD	26.5	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 0.00402% African / African-American · 3/74,586 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000186% 3/1,609,974 alleles · very rare

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.Met467Thr
Coding: c.1400T>C
MANE Select: NM_012287
dbSNP: rs1161438810
Type: single nucleotide variant
Location: chr3:195297277 (GRCh38)
Gene constraint: LOEUF 0.47 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 81.71 · 1 PDB
Residue 467: the arf-gap 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.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-met467thr (accessed [today's date]).

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