Is ETFB p.Arg21Gln (c.62G>A) pathogenic?

ETFB p.Arg21Gln (c.62G>A) is classified Uncertain significance in ETFB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-10). AlphaMissense: likely pathogenic (0.6282); Very rare (popmax 0.00667%, amr); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFB p.Arg21Gln (c.62G>A)?

ETFB p.Arg21Gln (c.62G>A) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFB p.Arg21Gln (c.62G>A) in the general population?

ETFB p.Arg21Gln (c.62G>A) is very rare (popmax 0.00667%, amr) (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.Arg21Gln (c.62G>A)?

AlphaMissense predicts likely pathogenic (score 0.6282) — an in-silico prediction, not a clinical call.

ETFB p.Arg21Gln

c.62G>A · rs369216610 · VCV1478109

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6282 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.6282	likely pathogenic
REVEL	0.695	pathogenic-leaning
SaProt	LLR -11.56	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.2, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 21 kb · p 0.0022 · regional, not allelic
Overall
CADD	24.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00667% Admixed American · 4/60,004 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000991% 16/1,614,002 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
Remaining individualsnot grpmax-eligible	0.0016%	62,486
Finnishnot grpmax-eligible	0.00156%	63,988
European (non-Finnish)	0.000847%	118,004

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.Arg21Gln
Coding: c.62G>A
MANE Select: NM_001985
dbSNP: rs369216610
Type: single nucleotide variant
Location: chr19:51354304 (GRCh38)
Gene constraint: LOEUF 1.1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.19 · 4 PDB

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.Arg21Ter Pathogenic/Likely pathogenic ★★ same residue
ETFB p.Arg21= Likely benign ★ same residue
ETFB p.Arg21fs Pathogenic/Likely pathogenic ★★ same residue
ETFB p.Arg21Pro 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.Arg85Ter 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-arg21gln (accessed [today's date]).

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