Is ETFB p.Val8Ile (c.22G>A) pathogenic?

ETFB p.Val8Ile (c.22G>A) is classified Uncertain significance in ETFB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-06). AlphaMissense: ambiguous (0.3702); Ultra-rare (popmax 0.0167%, nfe); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFB p.Val8Ile (c.22G>A)?

ETFB p.Val8Ile (c.22G>A) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFB p.Val8Ile (c.22G>A) in the general population?

ETFB p.Val8Ile (c.22G>A) is ultra-rare (popmax 0.0167%, nfe) (gnomAD).

How is Multiple acyl-CoA dehydrogenase deficiency inherited?

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

What do computational predictors say about ETFB p.Val8Ile (c.22G>A)?

AlphaMissense predicts ambiguous (score 0.3702) — an in-silico prediction, not a clinical call.

ETFB p.Val8Ile

c.22G>A · rs531136177 · VCV1367070

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3702 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, nfe)

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.3702	ambiguous
REVEL	0.625	indeterminate
SaProt	LLR -10.51	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0022 · regional, not allelic
Overall
CADD	29.7	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 0.0167% European (non-Finnish) · 197/1,179,990 alleles

Filtering AF 0.0148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.014%

Overall 0.0134% 216/1,613,508 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0167%	5,990
Admixed American	0.0117%	8,575
Remaining individualsnot grpmax-eligible	0.0112%	8,918
African / African-American	0.00267%	37,519
East Asian	0.00223%	44,876
South Asian	0.0022%	45,523

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: ETFB
Protein: p.Val8Ile
Coding: c.22G>A
MANE Select: NM_001985
dbSNP: rs531136177
Type: single nucleotide variant
Location: chr19:51366305 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.19 · 4 PDB
Residue 8: a β-strand

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

Disease context

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

For Multiple acyl-CoA dehydrogenase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

ETFB p.Val8Leu Uncertain significance ★ ⚠ same residue
ETFB p.Val8= Likely benign ★ same residue
ETFB c.375+1G>A Likely pathogenic ★★ same condition
ETFB c.375+1G>T Likely pathogenic ★★ same condition
ETFB p.Arg164Gln Pathogenic/Likely pathogenic ★★ same condition
ETFB p.Arg21Ter Pathogenic/Likely pathogenic ★★ same condition
ETFB p.Arg85Ter Pathogenic/Likely pathogenic ★★ same condition
ETFB p.Cys42Arg Pathogenic/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/etfb-p-val8ile (accessed [today's date]).

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