Is ETFB p.Val181Met (c.541G>A) pathogenic?

ETFB p.Val181Met (c.541G>A) is classified Uncertain significance in ETFB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-25). AlphaMissense: ambiguous (0.4049); Ultra-rare (popmax 0.0749%, afr); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFB p.Val181Met (c.541G>A)?

ETFB p.Val181Met (c.541G>A) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFB p.Val181Met (c.541G>A) in the general population?

ETFB p.Val181Met (c.541G>A) is ultra-rare (popmax 0.0749%, afr) (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.Val181Met (c.541G>A)?

AlphaMissense predicts ambiguous (score 0.4049) — an in-silico prediction, not a clinical call.

ETFB p.Val181Met

c.541G>A · rs148443220 · VCV1406302

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4049 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0749%, afr)

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.4049	ambiguous
REVEL	0.603	indeterminate
SaProt	LLR -9.43	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0022 · regional, not allelic
Overall
CADD	26.1	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 0.0749% African / African-American · 56/74,728 alleles

Filtering AF 0.0592% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0535%

Overall 0.00382% 61/1,597,526 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0749%	1,334
Admixed American	0.00348%	28,731
Remaining individualsnot grpmax-eligible	0.00323%	30,929
European (non-Finnish)	8.53e-05%	1,172,040

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.Val181Met
Coding: c.541G>A
MANE Select: NM_001985
dbSNP: rs148443220
Type: single nucleotide variant
Location: chr19:51346956 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.19 · 4 PDB
Residue 181: 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 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
ETFB p.Gln136Ter Pathogenic/Likely pathogenic ★★ same condition
ETFB p.Glu60Ter 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-val181met (accessed [today's date]).

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