Is ACADVL p.Ser583Trp (c.1748C>G) pathogenic?

ACADVL p.Ser583Trp (c.1748C>G) is classified Pathogenic/Likely pathogenic in ACADVL (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.9836); Very rare (popmax 0.00228%, eas); Associated with ACADVL-related disorder.

What condition is associated with ACADVL p.Ser583Trp (c.1748C>G)?

ACADVL p.Ser583Trp (c.1748C>G) is associated with ACADVL-related disorder, very long chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADVL p.Ser583Trp (c.1748C>G) in the general population?

ACADVL p.Ser583Trp (c.1748C>G) is very rare (popmax 0.00228%, eas) (gnomAD).

What do computational predictors say about ACADVL p.Ser583Trp (c.1748C>G)?

AlphaMissense predicts likely pathogenic (score 0.9836) — an in-silico prediction, not a clinical call.

ACADVL p.Ser583Trp

c.1748C>G · rs1085307648 · VCV426482

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely pathogenic

0.9836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00228%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ACADVL-related disorder

Computational evidence

Protein change
AlphaMissense	0.9836	likely pathogenic ✓ concordant with ClinVar · top 6% in ACADVL
REVEL	0.781	moderately pathogenic-leaning
SaProt	LLR -16.39	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 5,109 bp · p 0.51 · regional, not allelic
Overall
CADD	29.0	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 0.00228% East Asian · 1/43,778 alleles

Filtering AF 0.000249% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00016%

Overall 0.000554% 8/1,444,792 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00228%	43,778
European (non-Finnish)	0.000598%	167,333

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: ACADVL
Protein: p.Ser583Trp
Coding: c.1748C>G
MANE Select: NM_000018
dbSNP: rs1085307648
Type: single nucleotide variant
Location: chr17:7224711 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.65 · 3 PDB
Residue 583: an α-helix; a UniProt-annotated variant site (in acadvld; loss of homodimerization; loss of localization to mitochondrial inner membrane)

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

Disease context

ACADVL-related disorder

Also linked: very long chain acyl-CoA dehydrogenase deficiency

Similar variants

ACADVL p.Ser583Leu Uncertain significance ★★★ ⚠ same residue
ACADVL p.Ser583Ala Likely pathogenic ★ ⚠ same residue
ACADVL p.Ser583Ter Likely pathogenic ★ same residue
ACADVL p.Ser583= Likely benign ★ same residue
ACADVL c.1077+1G>A Likely pathogenic ★★★ same condition
ACADVL c.1077+1G>T Likely pathogenic ★★★ same condition
ACADVL c.1077+2T>A Pathogenic ★★★ same condition
ACADVL c.1077+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/acadvl-p-ser583trp (accessed [today's date]).

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