Is ETFA p.Ile108fs (c.321_322del) pathogenic?

ETFA p.Ile108fs (c.321322del) is classified Pathogenic/Likely pathogenic in ETFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-23). Very rare (popmax 8.48e-05%, nfe); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA p.Ile108fs (c.321_322del)?

ETFA p.Ile108fs (c.321_322del) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Ile108fs (c.321_322del) in the general population?

ETFA p.Ile108fs (c.321_322del) is very rare (popmax 8.48e-05%, 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.Ile108fs

c.321_322del · rs866218814 · VCV1454663

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,636 alleles

Overall 0.000137% 2/1,461,416 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,482
European (non-Finnish)grpmax	8.48e-05%	1,179,636

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile108fs
Coding: c.321_322del
MANE Select: NM_000126
dbSNP: rs866218814
Type: Microsatellite
Location: chr15:76292460 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 108: the 'domain i' region; a β-strand

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.Ile108Asn Uncertain significance ★ ⚠ same residue
ETFA p.Ile108Thr Uncertain significance ★ ⚠ same residue
ETFA p.Ile108= Likely benign ★ same residue
ETFA p.His107fs Pathogenic/Likely pathogenic ★★ same condition
ETFA p.Glu198fs Pathogenic ★ same condition
ETFA p.Ile108Val Uncertain significance ★ ⚠ same residue
ETFA p.Val270del Conflicting classifications of pathogenicity ★ same condition
ETFA c.817-12_817-11del Likely benign ★ 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-ile108fs (accessed [today's date]).

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