Is ACADM p.Arg53His (c.158G>A) pathogenic?

ACADM p.Arg53His (c.158G>A) is classified Conflicting classifications of pathogenicity in ACADM (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-06). AlphaMissense: likely benign (0.2141); Very rare (popmax 0.00333%, amr); Associated with medium chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADM p.Arg53His (c.158G>A)?

ACADM p.Arg53His (c.158G>A) is associated with medium chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADM p.Arg53His (c.158G>A) in the general population?

ACADM p.Arg53His (c.158G>A) is very rare (popmax 0.00333%, amr) (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.Arg53His (c.158G>A)?

AlphaMissense predicts likely benign (score 0.2141) — an in-silico prediction, not a clinical call.

ACADM p.Arg53His

c.158G>A · rs754938068 · VCV226066

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.2141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

medium chain acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.2141	likely benign
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -4.75	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 38 kb · p 0.63 · regional, not allelic
Overall
CADD	28.3	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 0.00333% Admixed American · 2/60,018 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.00103% 15/1,461,722 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,009
South Asian	0.00329%	30,361
East Asian	0.00223%	44,834
Remaining individualsnot grpmax-eligible	0.0016%	62,500
Finnishnot grpmax-eligible	0.00156%	64,018
European (non-Finnish)	0.000593%	168,564

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.Arg53His
Coding: c.158G>A
MANE Select: NM_000016
dbSNP: rs754938068
Type: single nucleotide variant
Location: chr1:75732683 (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 53: a UniProt-annotated variant site (in acadmd); 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.Arg53Cys Pathogenic ★★ ⚠ same residue
ACADM p.Arg53Gly Likely pathogenic ★ 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

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-arg53his (accessed [today's date]).

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