Is ETFA c.451+1G>A pathogenic?

ETFA c.451+1G>A is classified Likely pathogenic in ETFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-11). Very rare (popmax 0.00135%, afr); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA c.451+1G>A?

ETFA c.451+1G>A is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA c.451+1G>A in the general population?

ETFA c.451+1G>A is very rare (popmax 0.00135%, afr) (gnomAD).

How is Multiple acyl-CoA dehydrogenase deficiency inherited?

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

ETFA c.451+1G>A

rs780367967 · VCV2675086

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

canonical splice-site (±1/±2)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	canonical splice-site (±1/±2)	predicted loss-of-function
Splicing
Splice region	donor +1	canonical splice dinucleotide (donor +1) · inside the BP7-excluded zone
SpliceAI	Δ1.00	donor loss, 1 bp away · masked 0 · deltas
Pangolin	Δ0.84	loss · gain 0.08 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 7.6	GERP 1.5, phastCons 1
Non-coding constraint	Z 0.69	1 kb window · o/e 0.94 · regional · uncalibrated
Overall
CADD	33.0	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 0.00135% African / African-American · 1/74,288 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00019% 3/1,581,486 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	74,288
European (non-Finnish)	0.000174%	575,195

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
Coding: c.451+1G>A
MANE Select: NM_000126
dbSNP: rs780367967
Type: single nucleotide variant
Location: chr15:76287845 (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

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 c.186+1G>A Likely pathogenic ★★ same condition
ETFA c.39+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
ETFA p.Arg122Lys Likely pathogenic ★★ same condition
ETFA p.Arg18Ter Pathogenic/Likely pathogenic ★★ same condition
ETFA p.Arg209Ter Pathogenic/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-c-451-plus-1g-a (accessed [today's date]).

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