Is ACADVL p.Pro89Ser (c.265C>T) pathogenic?

ACADVL p.Pro89Ser (c.265C>T) is classified Likely pathogenic in ACADVL (ClinVar, Expert panel, 3 submitters; last evaluated 2022-08-09). AlphaMissense: likely pathogenic (0.6608); Absent from gnomAD v4.1; Associated with very long chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADVL p.Pro89Ser (c.265C>T)?

ACADVL p.Pro89Ser (c.265C>T) is associated with very long chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADVL p.Pro89Ser (c.265C>T) in the general population?

ACADVL p.Pro89Ser (c.265C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ACADVL p.Pro89Ser (c.265C>T)?

AlphaMissense predicts likely pathogenic (score 0.6608) — an in-silico prediction, not a clinical call.

ACADVL p.Pro89Ser

Q: How is Very long chain acyl-CoA dehydrogenase deficiency inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.265C>T · rs2508253534 · VCV1707712

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6608 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

very long chain acyl-CoA dehydrogenase deficiency

ClinGen expert panel — ACADVL VCEP

Likely Pathogenic for very long chain acyl-CoA dehydrogenase deficiency. Applied ACMG criteria (verbatim):

PP4_Moderate PM2_Supporting PS3_Supporting PP3 PM3

Curation rationale (ClinGen, verbatim)

The c.265C>T variant in ACADVL is a missense variant predicted to cause substitution of proline by serine at amino acid 89 (p.Pro89Ser). This variant has been reported in two individuals with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency in the literature with either significantly reduced VLCAD activity or variably increased C14:1 acylcarnitine levels (PP4_moderate; PMIDs: 11914034, Russian Paper). In these same probands, the variant was detected once confirmed in-trans with a pathogenic variant (PM3; PMIDs: 11914034). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). Site-directed mutagenesis expression showed impaired VLCAD enzyme activity (PS3_supporting; PMIDs: 11914034). The computational predictor REVEL gives a score of 0.922, which is above the threshold of 0.75, evidence that correlates with impact to ACADVL function (PP3). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal recessive VLCAD deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PP4_Moderate, PM3, PM2_Supporting, PS3_Supporting, PP3 (ACADVL VCEP specifications version 1; approved November 8, 2021).

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.6608	likely pathogenic ✓ concordant with ClinVar
REVEL	0.922	moderately pathogenic-leaning
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 5,109 bp · p 0.51 · regional, not allelic
Overall
CADD	26.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ACADVL
Protein: p.Pro89Ser
Coding: c.265C>T
MANE Select: NM_000018
dbSNP: rs2508253534
Type: single nucleotide variant
Location: chr17:7220664 (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 89: the 'catalytic' region

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

Disease context

very long chain acyl-CoA dehydrogenase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Very long chain acyl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

ACADVL p.Pro89fs Likely pathogenic ★★★ 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
ACADVL c.1182+1G>A Likely pathogenic ★★★ same condition
ACADVL c.1269+1G>A Likely pathogenic ★★★ same condition
ACADVL c.1532+1G>A 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/acadvl-p-pro89ser (accessed [today's date]).

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