Is ACADM p.Phe103fs (c.306_307insG) pathogenic?

ACADM p.Phe103fs (c.306307insG) is classified Pathogenic/Likely pathogenic in ACADM (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-08). Very rare (popmax 0.000424%, nfe); Associated with medium chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADM p.Phe103fs (c.306_307insG)?

ACADM p.Phe103fs (c.306_307insG) is associated with medium chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADM p.Phe103fs (c.306_307insG) in the general population?

ACADM p.Phe103fs (c.306_307insG) is very rare (popmax 0.000424%, 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.Phe103fs

c.306_307insG · rs2100365750 · VCV1677079

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000424%, 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 5 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.009	GERP 0.5, phastCons 0.004

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,179,978 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,768 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.Phe103fs
Coding: c.306_307insG
MANE Select: NM_000016
dbSNP: rs2100365750
Type: Insertion
Location: chr1:75733547 (GRCh38)
Gene constraint: LOEUF 1.072 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 93.15 · 7 PDB
Residue 103: an α-helix

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.Phe103Leu Likely pathogenic ★ same residue
ACADM p.Phe103Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
ACADM p.Gly4fs Likely pathogenic ★ same condition
ACADM c.286+9_286+10insTTTTT Likely benign ★ same condition
ACADM c.849+14_849+15insCCAT Likely benign ★ same condition
ACADM c.850-3_850-2insTAAATACTTAAAAT Likely benign ★ same condition
ACADM c.850-3_850-2insTAAAAT Uncertain significance same condition
ACADM c.850-8_850-7insTATCTTAAAATACTTAA Uncertain significance 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-phe103fs (accessed [today's date]).

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