Is ACADM p.Arg206Cys (c.616C>T) pathogenic?

ACADM p.Arg206Cys (c.616C>T) is classified Pathogenic/Likely pathogenic in ACADM (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-08-06). AlphaMissense: ambiguous (0.488); Very rare (popmax 0.00333%, amr); Associated with ACADM-related disorder.

What condition is associated with ACADM p.Arg206Cys (c.616C>T)?

ACADM p.Arg206Cys (c.616C>T) is associated with ACADM-related disorder, medium chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADM p.Arg206Cys (c.616C>T) in the general population?

ACADM p.Arg206Cys (c.616C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ACADM p.Arg206Cys (c.616C>T)?

AlphaMissense predicts ambiguous (score 0.488) — an in-silico prediction, not a clinical call.

ACADM p.Arg206Cys

c.616C>T · rs373715782 · VCV92267

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

ambiguous

0.488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ACADM-related disorder

Computational evidence

Protein change
AlphaMissense	0.488	ambiguous
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -14.75	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.36	acceptor gain · deltas
Pangolin	Δ0.39	gain · loss 0.24 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 38 kb · p 0.63 · regional, not allelic
Overall
CADD	35.0	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 · 2/59,972 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00279% 45/1,613,298 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,986
South Asian	0.00329%	30,354
European (non-Finnish)	0.00322%	31,040
Remaining individualsnot grpmax-eligible	0.0032%	31,228

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.Arg206Cys
Coding: c.616C>T
MANE Select: NM_000016
dbSNP: rs373715782
Type: single nucleotide variant
Location: chr1:75745822 (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 206: a UniProt-annotated variant site (in acadmd); a β-strand

Full ACADM gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ACADM-related disorder

Also linked: medium chain acyl-CoA dehydrogenase deficiency

Similar variants

ACADM p.Arg206His Pathogenic/Likely pathogenic ★★ ⚠ same residue
ACADM p.Arg206Leu Pathogenic/Likely pathogenic ★★ same residue
ACADM p.Arg206= Likely benign ★ 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

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-arg206cys (accessed [today's date]).

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