Is ACADVL p.Ter656Arg (c.1966T>A) pathogenic?

ACADVL p.Ter656Arg (c.1966T>A) is classified Uncertain significance in ACADVL (ClinVar, Expert panel, 1 submitter; last evaluated 2022-09-23). Absent from gnomAD v4.1; Associated with very long chain acyl-CoA dehydrogenase deficiency.

What condition is associated with ACADVL p.Ter656Arg (c.1966T>A)?

ACADVL p.Ter656Arg (c.1966T>A) is associated with very long chain acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ACADVL p.Ter656Arg (c.1966T>A) in the general population?

ACADVL p.Ter656Arg (c.1966T>A) is absent from gnomAD v4.1 (gnomAD).

ACADVL p.Ter656Arg

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.1966T>A · rs2508376848 · VCV1707703

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 1 submitter

Consequence

stop-loss

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 PM4

Curation rationale (ClinGen, verbatim)

The c.1966T>A variant in ACADVL is a stop-loss predicted to result in a 32-aa peptide extension at the C-terminus (PM4). This variant has been identified in one individual as a heterozygote identified by abnormal newborn screening results suggestive of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency (PMID: 30194637). This study also showed reduced VLCAD activity in patient lymphocytes, however, this assay does not meet the requirements for use by the ClinGen ACADVL Variant Curation Expert Panel. This variant is absent from gnomAD v2.1.1 (PM2_Supporting).In summary, this variant meets the criteria to be classified as uncertain 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: (PM4, PM2_Supporting)

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 carries the signal.
Consequence	stop-loss	predicted loss-of-function
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.2, phastCons 1
Overall
CADD	17.98	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

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.Ter656Arg
Coding: c.1966T>A
MANE Select: NM_000018
dbSNP: rs2508376848
Type: single nucleotide variant
Location: chr17:7225095 (GRCh38)
Gene constraint: LOEUF 1.077 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 90.65 · 3 PDB

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.Ter656Cys Uncertain significance ★★★ same residue
ACADVL p.Ter656Ser 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

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-ter656arg (accessed [today's date]).

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