Is ACADM p.Ser22Ter (c.65C>A) pathogenic?

ACADM p.Ser22Ter (c.65C>A) is classified Pathogenic/Likely pathogenic in ACADM (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-03). Very rare (popmax 0.00549%, sas); Associated with medium chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADM p.Ser22Ter (c.65C>A)?

ACADM p.Ser22Ter (c.65C>A) is associated with medium chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADM p.Ser22Ter (c.65C>A) in the general population?

ACADM p.Ser22Ter (c.65C>A) is very rare (popmax 0.00549%, sas) (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.Ser22Ter

c.65C>A · rs1325609596 · VCV2023607

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00549%, sas)

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	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.25	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -0.04	GERP 0.024
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00549% South Asian · 5/91,046 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.000342% 5/1,461,208 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.Ser22Ter
Coding: c.65C>A
MANE Select: NM_000016
dbSNP: rs1325609596
Type: single nucleotide variant
Location: chr1:75728435 (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 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-ser22ter (accessed [today's date]).

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