Is ACAA2 p.Val378Ala (c.1133T>C) pathogenic?

ACAA2 p.Val378Ala (c.1133T>C) is classified Uncertain significance in ACAA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-05). AlphaMissense: likely benign (0.2977); Very rare (popmax 0.00167%, amr).

How common is ACAA2 p.Val378Ala (c.1133T>C) in the general population?

ACAA2 p.Val378Ala (c.1133T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about ACAA2 p.Val378Ala (c.1133T>C)?

AlphaMissense predicts likely benign (score 0.2977) — an in-silico prediction, not a clinical call.

ACAA2 p.Val378Ala

c.1133T>C · VCV4636542

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2977 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2977	likely benign
REVEL	0.584	indeterminate
SaProt	LLR -8.93	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.8	phastCons 0.87
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	18.59	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 0.00167% Admixed American · 1/60,010 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,006 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,010
European (non-Finnish)	0.000254%	393,329

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: ACAA2
Protein: p.Val378Ala
Coding: c.1133T>C
MANE Select: NM_006111
Type: single nucleotide variant
Location: chr18:49783908 (GRCh38)
Gene constraint: LOEUF 1.148 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.49 · 2 PDB
Residue 378: a β-strand

Full ACAA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAA2 p.Val378Leu Uncertain significance ★ ⚠ same residue
ACAA2 p.Val378Ile Likely benign ★ same residue
ACAA2 p.Tyr198Asn Benign ★★ same type
ACAA2 p.Ala183Thr Uncertain significance ★ ⚠ same type
ACAA2 p.Ala196Thr Uncertain significance ★ ⚠ same type
ACAA2 p.Ala250Thr Uncertain significance ★ ⚠ same type
ACAA2 p.Ala267Gly Uncertain significance ★ ⚠ same type
ACAA2 p.Ala70Ser 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/acaa2-p-val378ala (accessed [today's date]).

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