Is ACADS p.Arg46Trp (c.136C>T) pathogenic?

ACADS p.Arg46Trp (c.136C>T) is classified Pathogenic/Likely pathogenic in ACADS (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-05-30). AlphaMissense: ambiguous (0.3507); Ultra-rare (popmax 0.0922%, sas); Associated with ACADS-related disorder.

What condition is associated with ACADS p.Arg46Trp (c.136C>T)?

ACADS p.Arg46Trp (c.136C>T) is associated with ACADS-related disorder, short chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADS p.Arg46Trp (c.136C>T) in the general population?

ACADS p.Arg46Trp (c.136C>T) is ultra-rare (popmax 0.0922%, sas) (gnomAD).

What do computational predictors say about ACADS p.Arg46Trp (c.136C>T)?

AlphaMissense predicts ambiguous (score 0.3507) — an in-silico prediction, not a clinical call.

ACADS p.Arg46Trp

c.136C>T · rs121908003 · VCV3825

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

ambiguous

0.3507 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0922%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

ACADS-related disorder

Computational evidence

Protein change
AlphaMissense	0.3507	ambiguous
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -13.49	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 3.7	GERP 0.84, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 14 kb · p 0.038 · regional, not allelic
Overall
CADD	31.0	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 0.0922% South Asian · 84/91,082 alleles

Filtering AF 0.0763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0704%

Overall 0.0109% 176/1,614,172 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0922%	1,084
Admixed American	0.0367%	2,728
Middle Eastern	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.008%	12,501
European (non-Finnish)	0.00534%	18,731
East Asian	0.00223%	44,876

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: ACADS
Protein: p.Arg46Trp
Coding: c.136C>T
MANE Select: NM_000017
dbSNP: rs121908003
Type: single nucleotide variant
Location: chr12:120727115 (GRCh38)
Gene constraint: LOEUF 0.852 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.58 · 4 PDB
Residue 46: a UniProt-annotated variant site (in acadsd); an α-helix

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

Disease context

ACADS-related disorder

Also linked: short chain acyl-CoA dehydrogenase deficiency

Similar variants

ACADS p.Arg46Gln Likely pathogenic ★ ⚠ same residue
ACADS c.211-2A>G Likely pathogenic ★★ same condition
ACADS c.625-1G>A Likely pathogenic ★★ same condition
ACADS c.795+1G>A Pathogenic/Likely pathogenic ★★ same condition
ACADS p.Ala199Val Likely pathogenic ★★ ⚠ same condition
ACADS p.Arg107Cys Pathogenic ★★ ⚠ same condition
ACADS p.Arg272Cys Pathogenic/Likely pathogenic ★★ same condition
ACADS p.Arg325Gln 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/acads-p-arg46trp (accessed [today's date]).

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