Is ACADM p.Pro229fs (c.686del) pathogenic?

ACADM p.Pro229fs (c.686del) is classified Pathogenic/Likely pathogenic in ACADM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-20). Very rare (popmax 8.48e-05%, nfe); Associated with medium chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADM p.Pro229fs (c.686del)?

ACADM p.Pro229fs (c.686del) is associated with medium chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADM p.Pro229fs (c.686del) in the general population?

ACADM p.Pro229fs (c.686del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Medium chain acyl-CoA dehydrogenase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

ACADM p.Pro229fs

c.686del · rs1647873033 · VCV862822

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

medium chain acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	GERP -0.91, phastCons 0.99

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,190 alleles

Overall 6.85e-05% 1/1,460,818 alleles · very rare

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.Pro229fs
Coding: c.686del
MANE Select: NM_000016
dbSNP: rs1647873033
Type: Deletion
Location: chr1:75745889 (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

medium chain acyl-CoA dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Medium chain acyl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

ACADM p.Pro229= Likely benign ★ same residue
ACADM c.217-1del Likely pathogenic ★★ same condition
ACADM p.Ala273fs Pathogenic/Likely pathogenic ★★ same condition
ACADM p.Ala369fs Pathogenic/Likely pathogenic ★★ same condition
ACADM p.Arg348fs Pathogenic/Likely pathogenic ★★ same condition
ACADM p.Arg408fs Pathogenic/Likely pathogenic ★★ same condition
ACADM p.Arg413fs Likely pathogenic ★★ same condition
ACADM p.Glu260fs 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-pro229fs (accessed [today's date]).

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