Is ETFA p.Arg18Ter (c.52C>T) pathogenic?

ETFA p.Arg18Ter (c.52C>T) is classified Pathogenic/Likely pathogenic in ETFA (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-06-01). Ultra-rare (popmax 0.0121%, sas); Associated with Glutaric acidemia type 2A.

What condition is associated with ETFA p.Arg18Ter (c.52C>T)?

ETFA p.Arg18Ter (c.52C>T) is associated with Glutaric acidemia type 2A, multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Arg18Ter (c.52C>T) in the general population?

ETFA p.Arg18Ter (c.52C>T) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

ETFA p.Arg18Ter

c.52C>T · rs754202690 · VCV666198

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Conditions

Glutaric acidemia type 2A

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 2 of 12
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP -0.48, phastCons 1
Overall
CADD	39.0	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 0.0121% South Asian · 11/90,984 alleles

Filtering AF 0.00677% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.0046% 74/1,609,326 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,271
European (non-Finnish)	0.00484%	20,678
East Asian	0.00447%	22,364
Remaining individualsnot grpmax-eligible	0.00321%	31,165
Admixed American	0.00168%	59,564
African / African-American	0.00135%	73,842

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.Arg18Ter
Coding: c.52C>T
MANE Select: NM_000126
dbSNP: rs754202690
Type: single nucleotide variant
Location: chr15:76295725 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB

Full ETFA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Glutaric acidemia type 2A

Also linked: multiple acyl-CoA dehydrogenase deficiency

Similar variants

ETFA p.Arg18Gln Uncertain significance ★ ⚠ same residue
ETFA p.Arg18= Likely benign ★ same residue
MADD p.Val18Ile 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

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-arg18ter (accessed [today's date]).

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