Is ACAA2 p.Val378Ile (c.1132G>A) pathogenic?

ACAA2 p.Val378Ile (c.1132G>A) is classified Likely benign in ACAA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-21). AlphaMissense: likely benign (0.086); Ultra-rare (popmax 0.0331%, mid).

How common is ACAA2 p.Val378Ile (c.1132G>A) in the general population?

ACAA2 p.Val378Ile (c.1132G>A) is ultra-rare (popmax 0.0331%, mid) (gnomAD).

What do computational predictors say about ACAA2 p.Val378Ile (c.1132G>A)?

AlphaMissense predicts likely benign (score 0.086) — an in-silico prediction, not a clinical call.

ACAA2 p.Val378Ile

c.1132G>A · rs142211915 · VCV2208325

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0331%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.086	likely benign
REVEL	0.249	benign-leaning
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.24
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	0.057	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 0.0331% Middle Eastern · 2/6,050 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00785%

Overall 0.00657% 106/1,613,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0331%	3,025
Admixed American	0.0183%	5,457
Remaining individualsnot grpmax-eligible	0.0096%	10,416
European (non-Finnish)	0.00737%	13,562

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.Val378Ile
Coding: c.1132G>A
MANE Select: NM_006111
dbSNP: rs142211915
Type: single nucleotide variant
Location: chr18:49783909 (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.Val378Ala Uncertain significance ★ ⚠ same residue
ACAA2 p.Val378Leu Uncertain significance ★ ⚠ 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-val378ile (accessed [today's date]).

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