Is ACAP3 p.Ala685Val (c.2054C>T) pathogenic?

ACAP3 p.Ala685Val (c.2054C>T) is classified Uncertain significance in ACAP3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.2393); Ultra-rare (popmax 0.019%, amr).

How common is ACAP3 p.Ala685Val (c.2054C>T) in the general population?

ACAP3 p.Ala685Val (c.2054C>T) is ultra-rare (popmax 0.019%, amr) (gnomAD).

What do computational predictors say about ACAP3 p.Ala685Val (c.2054C>T)?

AlphaMissense predicts likely benign (score 0.2393) — an in-silico prediction, not a clinical call.

ACAP3 p.Ala685Val

c.2054C>T · rs771214380 · VCV2330081

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2393 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.019%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2393	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -12.37	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 0.52, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 14 kb · p 0.33 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.019% Admixed American · 10/52,610 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00777%

Overall 0.00104% 16/1,545,654 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.019%	5,261
Remaining individualsnot grpmax-eligible	0.00501%	19,953
Finnishnot grpmax-eligible	0.00415%	24,084
East Asian	0.00244%	40,982

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: ACAP3
Protein: p.Ala685Val
Coding: c.2054C>T
MANE Select: NM_030649
dbSNP: rs771214380
Type: single nucleotide variant
Location: chr1:1294487 (GRCh38)
Gene constraint: LOEUF 0.816 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.31

Full ACAP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAP3 p.Ala242Val Uncertain significance ★ ⚠ same type
ACAP3 p.Ala265Val Uncertain significance ★ ⚠ same type
ACAP3 p.Ala282Thr Uncertain significance ★ ⚠ same type
ACAP3 p.Ala307Thr Uncertain significance ★ ⚠ same type
ACAP3 p.Ala392Thr Uncertain significance ★ ⚠ same type
ACAP3 p.Ala526Thr Uncertain significance ★ ⚠ same type
ACAP3 p.Ala596Val Uncertain significance ★ ⚠ same type
ACAP3 p.Ala598Thr 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/acap3-p-ala685val (accessed [today's date]).

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