Is ACAA1 p.Asp75Glu (c.225C>G) pathogenic?

ACAA1 p.Asp75Glu (c.225C>G) is classified Likely benign in ACAA1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2023-04-05). AlphaMissense: ambiguous (0.3512); Rare (popmax 0.296%, afr); Associated with ACAA1-related disorder.

What condition is associated with ACAA1 p.Asp75Glu (c.225C>G)?

ACAA1 p.Asp75Glu (c.225C>G) is associated with ACAA1-related disorder (ClinVar).

How common is ACAA1 p.Asp75Glu (c.225C>G) in the general population?

ACAA1 p.Asp75Glu (c.225C>G) is rare (popmax 0.296%, afr) (gnomAD).

What do computational predictors say about ACAA1 p.Asp75Glu (c.225C>G)?

AlphaMissense predicts ambiguous (score 0.3512) — an in-silico prediction, not a clinical call.

ACAA1 p.Asp75Glu

c.225C>G · rs147670996 · VCV3043793

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3512 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.296%, afr)

Conditions

ACAA1-related disorder

Computational evidence

Protein change
AlphaMissense	0.3512	ambiguous
REVEL	0.443	indeterminate
SaProt	LLR -7.43	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.56	GERP -3, phastCons 0.04
Regional constraint	o/e 0.91	unconstrained · MANE · 14 kb · p 0.034 · regional, not allelic
Overall
CADD	11.12	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 0.296% African / African-American · 222/75,040 alleles

Filtering AF 0.264% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.252%

Overall 0.0258% 417/1,613,996 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.296%	338
Middle Eastern	0.099%	1,010
Admixed American	0.0983%	1,017
Remaining individualsnot grpmax-eligible	0.072%	1,389
European (non-Finnish)	0.0072%	13,882

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.Asp75Glu
Coding: c.225C>G
MANE Select: NM_001607
dbSNP: rs147670996
Type: single nucleotide variant
Location: chr3:38136632 (GRCh38)
Gene constraint: LOEUF 1.199 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.93 · 2 PDB
Residue 75: an α-helix

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

Disease context

ACAA1-related disorder

Similar variants

ACAA1 c.546-4C>A Likely benign same condition
ACAA1 c.627-9T>C Likely benign same condition
ACAA1 p.Asp85= Likely benign same condition
ACAA1 p.Gln2= Likely benign same condition
ACAA1 p.Pro368= Likely benign same condition
ACAA1 p.Ser154= Benign same condition
ACAA1 p.Glu172Asp Benign ★★ ⚠ same type
ACAA1 p.Ala131Ser 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-asp75glu (accessed [today's date]).

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