Is ACAA2 p.Val114Leu (c.340G>C) pathogenic?

ACAA2 p.Val114Leu (c.340G>C) is classified Uncertain significance in ACAA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-28). AlphaMissense: ambiguous (0.4811); Absent from gnomAD v4.1.

How common is ACAA2 p.Val114Leu (c.340G>C) in the general population?

ACAA2 p.Val114Leu (c.340G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACAA2 p.Val114Leu (c.340G>C)?

AlphaMissense predicts ambiguous (score 0.4811) — an in-silico prediction, not a clinical call.

ACAA2 p.Val114Leu

c.340G>C · VCV3995454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4811 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4811	ambiguous
REVEL	0.73	pathogenic-leaning
SaProt	LLR -9.54	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 30 kb · p 0.51 · regional, not allelic
Overall
CADD	23.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACAA2
Protein: p.Val114Leu
Coding: c.340G>C
MANE Select: NM_006111
Type: single nucleotide variant
Location: chr18:49795854 (GRCh38)
Gene constraint: LOEUF 1.148 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.49 · 2 PDB
Residue 114: a β-strand

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

Similar variants

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
ACAA2 p.Arg133His Uncertain significance ★ ⚠ same type
ACAA2 p.Arg371Cys 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-val114leu (accessed [today's date]).

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