Is ETFA p.Asp253= (c.759T>C) pathogenic?

ETFA p.Asp253= (c.759T>C) is classified Likely benign in ETFA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-09-04). Very rare (popmax 0.00263%, nfe); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA p.Asp253= (c.759T>C)?

ETFA p.Asp253= (c.759T>C) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Asp253= (c.759T>C) in the general population?

ETFA p.Asp253= (c.759T>C) is very rare (popmax 0.00263%, 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.Asp253=

c.759T>C · rs142970498 · VCV799678

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.54, phastCons 1
Overall
CADD	8.265	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% European (non-Finnish) · 31/1,179,322 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00198% 32/1,612,684 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00263%	38,043
Remaining individualsnot grpmax-eligible	0.0016%	62,448

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.Asp253=
Coding: c.759T>C
MANE Select: NM_000126
dbSNP: rs142970498
Type: single nucleotide variant
Location: chr15:76274469 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 253: the 'domain ii' region; 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.Asp253Val Uncertain significance ★ ⚠ same residue
MADD p.Arg253Gln 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-asp253 (accessed [today's date]).

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