Is ETFA p.Arg223= (c.667C>A) pathogenic?

ETFA p.Arg223= (c.667C>A) is classified Likely benign in ETFA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-25). Very rare (popmax 0.000255%, nfe); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA p.Arg223= (c.667C>A)?

ETFA p.Arg223= (c.667C>A) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Arg223= (c.667C>A) in the general population?

ETFA p.Arg223= (c.667C>A) is very rare (popmax 0.000255%, nfe) (gnomAD).

How is Multiple acyl-CoA dehydrogenase deficiency inherited?

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

ETFA p.Arg223=

c.667C>A · rs769976586 · VCV1152930

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.89	acceptor gain · deltas
Pangolin	Δ0.75	gain · loss 0.40 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000255% European (non-Finnish) · 3/1,175,144 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000206% 3/1,455,144 alleles · very rare

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: ETFA
Protein: p.Arg223=
Coding: c.667C>A
MANE Select: NM_000126
dbSNP: rs769976586
Type: single nucleotide variant
Location: chr15:76283823 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 223: the 'domain ii' region; a binding site; an α-helix

Full ETFA 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

ETFA p.Arg223Ter Pathogenic/Likely pathogenic ★★ same residue
ETFA p.Arg223Gln Uncertain significance ★★ ⚠ same residue
ETFA c.186+1G>A Likely pathogenic ★★ same condition
ETFA c.39+1G>A Likely pathogenic ★★ same condition
ETFA c.451+1G>A Likely pathogenic ★★ same condition
ETFA c.452-2A>G Likely pathogenic ★★ same condition
ETFA c.664+1G>A Likely pathogenic ★★ same condition
ETFA c.665-1G>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/etfa-p-arg223 (accessed [today's date]).

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