Is ACADVL p.Ala359= (c.1077G>A) pathogenic?

ACADVL p.Ala359= (c.1077G>A) is classified Uncertain significance in ACADVL (ClinVar, Expert panel, 8 submitters; last evaluated 2025-10-28). Very rare (popmax 0.00668%, eas); Associated with very long chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADVL p.Ala359= (c.1077G>A)?

ACADVL p.Ala359= (c.1077G>A) is associated with very long chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADVL p.Ala359= (c.1077G>A) in the general population?

ACADVL p.Ala359= (c.1077G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

ACADVL p.Ala359=

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.1077G>A · rs779458466 · VCV541717

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Conditions

very long chain acyl-CoA dehydrogenase deficiency

ClinGen expert panel — ACADVL VCEP

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

PM2_Supporting

Curation rationale (ClinGen, verbatim)

The NM_000018.4(ACADVL):c.1077G>A (p.Ala359=) variant is a synonymous (silent) variant is located in the last nucleotide position of exon 10 in ACADVL. Although it is adjacent to the canonical donor site in intron 10 and may potentially generate a cryptic donor gain, it does not meet the ACADVL VCEP’s criteria to be predicted to impact splicing (SpliceAI donor gain 0.45). The highest population minor allele frequency in gnomAD v4.1.0 is 0.000067 in East Asian population, which is lower than the ClinGen ACADVL Variant Curation Expert Panel threshold (<0.001) for PM2_Supporting, meeting this criterion (PM2_Supporting). This variant was detected in at least two individuals during abnormal newborn screening (PMIDs: 26385305, 31737040). In addition, this variant was also identified in homozygous fashion in a patient with abnormal newborn screening (PMID: 27246109). However, without further supporting data, this information is insufficient to be used toward classification. Due to limited evidence, this variant is classified as a variant of uncertain significance for autosomal recessive very long chain acyl-CoA dehydrogenase (VLCAD) deficiency based on the ACMG/AMP criteria applied, as specified by the ClinGen ACADVL Variant Curation Expert Panel: PM2_Supporting (ACADVL VCEP specifications version 2; approved May 01, 2025).

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.45	donor gain · deltas
Pangolin	Δ0.38	gain · loss 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP -0.12	GERP -3, phastCons 0.007
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00668% East Asian · 3/44,898 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00124% 20/1,610,946 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,966
Remaining individualsnot grpmax-eligible	0.0016%	62,336
European (non-Finnish)	0.00127%	78,664
South Asian	0.0011%	90,986

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.Ala359=
Coding: c.1077G>A
MANE Select: NM_000018
dbSNP: rs779458466
Type: single nucleotide variant
Location: chr17:7222865 (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 359: an α-helix; the 'catalytic' region; a UniProt-annotated variant site (in)

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.Ala359Val Pathogenic/Likely pathogenic ★★ ⚠ same residue
ACADVL p.Ala359fs 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

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-ala359 (accessed [today's date]).

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