Is ACADVL p.Ser207Pro (c.619T>C) pathogenic?

ACADVL p.Ser207Pro (c.619T>C) is classified Likely pathogenic in ACADVL (ClinVar, Expert panel, 8 submitters; last evaluated 2024-02-27). AlphaMissense: likely pathogenic (0.6662); Ultra-rare (popmax 0.0111%, eas); Associated with very long chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADVL p.Ser207Pro (c.619T>C)?

ACADVL p.Ser207Pro (c.619T>C) is associated with very long chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADVL p.Ser207Pro (c.619T>C) in the general population?

ACADVL p.Ser207Pro (c.619T>C) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about ACADVL p.Ser207Pro (c.619T>C)?

AlphaMissense predicts likely pathogenic (score 0.6662) — an in-silico prediction, not a clinical call.

ACADVL p.Ser207Pro

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.619T>C · rs768975918 · VCV551588

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely pathogenic

0.6662 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

3/3 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):

PM2_Supporting PP4_Moderate PM3_Strong PP3

Curation rationale (ClinGen, verbatim)

The NM_000018.4(ACADVL): c.619T>C (p.Ser207Pro) variant is a missense variant predicted to cause substitution of serine by proline at amino acid 207. At least two individuals with this variant displayed a newborn screen consistent with very long chain acyl-CoA dehydrogenase (VLCAD) deficiency as well as follow-up acylcarnitine testing showing increased C14:1 acylcarnitines, which is highly specific for VLCAD deficiency (PP4_Moderate, PMID: 26927351). This individual was compound heterozygous for this variant and a distinct pathogenic or likely pathogenic variant confirmed in trans by parental testing (PM3_Strong). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.79, 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: PM2_Supporting, PM3_Strong, PP3, PP4_Moderate (ACADVL VCEP specifications version 1; approved November 9, 2021).

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

Computational evidence

Protein change
AlphaMissense	0.6662	likely pathogenic ✓ concordant with ClinVar
REVEL	0.792	moderately pathogenic-leaning
SaProt	LLR -11.57	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 2.3	GERP -1.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 5,109 bp · p 0.51 · regional, not allelic
Overall
CADD	24.1	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 0.0111% East Asian · 5/44,888 alleles

Filtering AF 0.00434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000411% 6/1,461,470 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,978
European (non-Finnish)	8.47e-05%	1,180,038

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.Ser207Pro
Coding: c.619T>C
MANE Select: NM_000018
dbSNP: rs768975918
Type: single nucleotide variant
Location: chr17:7221679 (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 207: an α-helix; 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.Ser207Ala Uncertain significance ⚠ 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-ser207pro (accessed [today's date]).

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