Is ACADM p.Leu84Phe (c.250C>T) pathogenic?

ACADM p.Leu84Phe (c.250C>T) is classified Pathogenic/Likely pathogenic in ACADM (ClinVar, Multiple submitters, 13 submitters; last evaluated 2026-01-12). AlphaMissense: ambiguous (0.3538); Ultra-rare (popmax 0.0127%, nfe); Associated with medium chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADM p.Leu84Phe (c.250C>T)?

ACADM p.Leu84Phe (c.250C>T) is associated with medium chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADM p.Leu84Phe (c.250C>T) in the general population?

ACADM p.Leu84Phe (c.250C>T) is ultra-rare (popmax 0.0127%, 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.

What do computational predictors say about ACADM p.Leu84Phe (c.250C>T)?

AlphaMissense predicts ambiguous (score 0.3538) — an in-silico prediction, not a clinical call.

ACADM p.Leu84Phe

c.250C>T · rs762114560 · VCV226097

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

ambiguous

0.3538 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0127%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

medium chain acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.3538	ambiguous
REVEL	0.92	moderately pathogenic-leaning
SaProt	LLR -13.48	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 38 kb · p 0.63 · regional, not allelic
Overall
CADD	27.3	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 0.0127% European (non-Finnish) · 150/1,179,878 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0104%

Overall 0.0101% 163/1,613,818 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0127%	7,866
Admixed American	0.00833%	12,000
African / African-American	0.00534%	18,730
Remaining individualsnot grpmax-eligible	0.0048%	20,825
East Asian	0.00223%	44,860

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.Leu84Phe
Coding: c.250C>T
MANE Select: NM_000016
dbSNP: rs762114560
Type: single nucleotide variant
Location: chr1:75732886 (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.Leu84Ile Uncertain significance ⚠ same residue
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

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-leu84phe (accessed [today's date]).

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