Is ETFA p.Arg223Ter (c.667C>T) pathogenic?

ETFA p.Arg223Ter (c.667C>T) is classified Pathogenic/Likely pathogenic in ETFA (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-01-27). Very rare (popmax 0.00468%, nfe); Associated with ETFA-related disorders.

What condition is associated with ETFA p.Arg223Ter (c.667C>T)?

ETFA p.Arg223Ter (c.667C>T) is associated with ETFA-related disorders, multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Arg223Ter (c.667C>T) in the general population?

ETFA p.Arg223Ter (c.667C>T) is very rare (popmax 0.00468%, nfe) (gnomAD).

ETFA p.Arg223Ter

c.667C>T · rs769976586 · VCV429752

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00468%, nfe)

Conditions

ETFA-related disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 12
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.89 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Overall
CADD	45.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00468% European (non-Finnish) · 55/1,175,146 alleles

Filtering AF 0.00368% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0033%

Overall 0.00355% 57/1,606,390 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00468%	21,366
Remaining individualsnot grpmax-eligible	0.00321%	31,121

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.Arg223Ter
Coding: c.667C>T
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

ETFA-related disorders

Also linked: multiple acyl-CoA dehydrogenase deficiency

Similar variants

ETFA p.Arg223Gln Uncertain significance ★★ ⚠ same residue
ETFA p.Arg223= Likely benign ★ 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-arg223ter (accessed [today's date]).

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