Is ACADM p.Ala226= (c.678A>G) pathogenic?

ACADM p.Ala226= (c.678A>G) is classified Benign/Likely benign in ACADM (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). Low-frequency (popmax 2.29%, amr); Associated with Inborn genetic diseases.

What condition is associated with ACADM p.Ala226= (c.678A>G)?

ACADM p.Ala226= (c.678A>G) is associated with Inborn genetic diseases, medium chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADM p.Ala226= (c.678A>G) in the general population?

ACADM p.Ala226= (c.678A>G) is low-frequency (popmax 2.29%, amr) (gnomAD).

ACADM p.Ala226=

c.678A>G · rs2229249 · VCV226082

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

low-frequency (popmax 2.29%, amr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -1.4, phastCons 0.63
Overall
CADD	7.181	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.29% Admixed American · 1,373/60,022 alleles

Filtering AF 2.19% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.15%

Overall 0.0888% 1,433/1,613,438 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	2.29%	44
Remaining individualsnot grpmax-eligible	0.056%	1,785
African / African-American	0.02%	5,002
European (non-Finnish)	0.000848%	117,945

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: ACADM
Protein: p.Ala226=
Coding: c.678A>G
MANE Select: NM_000016
dbSNP: rs2229249
Type: single nucleotide variant
Location: chr1:75745884 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.15 · 7 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: medium chain acyl-CoA dehydrogenase deficiency

Similar variants

ACADM c.118+1G>T Likely pathogenic ★★ same condition
ACADM c.1194+1G>A Pathogenic/Likely pathogenic ★★ same condition
ACADM c.1194+2T>G Likely pathogenic ★★ same condition
ACADM c.216+1G>A Pathogenic ★★ same condition
ACADM c.216+1G>T Pathogenic/Likely pathogenic ★★ same condition
ACADM c.216+2T>C Pathogenic ★★ same condition
ACADM c.216+2T>G Pathogenic ★★ same condition
ACADM c.217-1G>A Pathogenic/Likely pathogenic ★★ same condition

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/acadm-p-ala226 (accessed [today's date]).

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