Is ACAA1 p.Val418Ile (c.1252G>A) pathogenic?

ACAA1 p.Val418Ile (c.1252G>A) is classified Uncertain significance in ACAA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely benign (0.0994); Ultra-rare (popmax 0.0657%, mid).

How common is ACAA1 p.Val418Ile (c.1252G>A) in the general population?

ACAA1 p.Val418Ile (c.1252G>A) is ultra-rare (popmax 0.0657%, mid) (gnomAD).

What do computational predictors say about ACAA1 p.Val418Ile (c.1252G>A)?

AlphaMissense predicts likely benign (score 0.0994) — an in-silico prediction, not a clinical call.

ACAA1 p.Val418Ile

c.1252G>A · VCV3454631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0994 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0657%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0994	likely benign
REVEL	0.53	indeterminate
SaProt	LLR -10.71	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 2	GERP 1.8, phastCons 0.95
Regional constraint	o/e 0.91	unconstrained · MANE · 14 kb · p 0.034 · regional, not allelic
Overall
CADD	21.7	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 0.0657% Middle Eastern · 4/6,084 alleles

Filtering AF 0.0224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.00316% 51/1,614,042 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0657%	1,521
African / African-American	0.024%	4,163
East Asian	0.0111%	8,979
Remaining individualsnot grpmax-eligible	0.008%	12,498
Admixed American	0.00333%	30,000
South Asian	0.0022%	45,544
European (non-Finnish)	0.00127%	78,668

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: ACAA1
Protein: p.Val418Ile
Coding: c.1252G>A
MANE Select: NM_001607
Type: single nucleotide variant
Location: chr3:38123070 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.93 · 2 PDB
Residue 418: a β-strand

Full ACAA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ACAA1 p.Glu172Asp Benign ★★ ⚠ same type
ACAA1 p.Ala131Ser Uncertain significance ★ ⚠ same type
ACAA1 p.Ala24Val Uncertain significance ★ ⚠ same type
ACAA1 p.Ala324Gly Uncertain significance ★ ⚠ same type
ACAA1 p.Ala33Thr Uncertain significance ★ ⚠ same type
ACAA1 p.Ala416Thr Uncertain significance ★ ⚠ same type
ACAA1 p.Arg167Cys Uncertain significance ★ ⚠ same type
ACAA1 p.Arg167His 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/acaa1-p-val418ile (accessed [today's date]).

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