Is ETFB p.Arg174His (c.521G>A) pathogenic?

ETFB p.Arg174His (c.521G>A) is classified Likely benign in ETFB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-15). AlphaMissense: likely benign (0.0682); Rare (popmax 0.497%, afr); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFB p.Arg174His (c.521G>A)?

ETFB p.Arg174His (c.521G>A) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFB p.Arg174His (c.521G>A) in the general population?

ETFB p.Arg174His (c.521G>A) is rare (popmax 0.497%, 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.Arg174His (c.521G>A)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

ETFB p.Arg174His

c.521G>A · rs141917423 · VCV203699

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.497%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.364	indeterminate
SaProt	LLR -5.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0022 · regional, not allelic
Overall
CADD	23.4	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 0.497% African / African-American · 372/74,878 alleles

Filtering AF 0.455% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.439%

Overall 0.0247% 398/1,608,744 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.497%	201
Admixed American	0.0169%	5,931
Remaining individualsnot grpmax-eligible	0.0161%	6,230
South Asian	0.00111%	89,816
European (non-Finnish)	0.000425%	235,562

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.Arg174His
Coding: c.521G>A
MANE Select: NM_001985
dbSNP: rs141917423
Type: single nucleotide variant
Location: chr19:51346976 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.19 · 4 PDB
Residue 174: 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.Arg174Cys Uncertain significance ★★ ⚠ same residue
ETFB p.Arg174Gly Uncertain significance ★ ⚠ 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-arg174his (accessed [today's date]).

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