Is ETFA p.Pro7Leu (c.20C>T) pathogenic?

ETFA p.Pro7Leu (c.20C>T) is classified Conflicting classifications of pathogenicity in ETFA (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-03-05). AlphaMissense: likely benign (0.194); Ultra-rare (popmax 0.053%, nfe); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA p.Pro7Leu (c.20C>T)?

ETFA p.Pro7Leu (c.20C>T) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Pro7Leu (c.20C>T) in the general population?

ETFA p.Pro7Leu (c.20C>T) is ultra-rare (popmax 0.053%, nfe) (gnomAD).

How is Multiple acyl-CoA dehydrogenase deficiency inherited?

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

What do computational predictors say about ETFA p.Pro7Leu (c.20C>T)?

AlphaMissense predicts likely benign (score 0.194) — an in-silico prediction, not a clinical call.

ETFA p.Pro7Leu

c.20C>T · rs557160401 · VCV203689

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.194 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.053%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.194	likely benign
REVEL	0.154	moderately benign-leaning
SaProt	LLR -3.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.3, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	18.73	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.053% European (non-Finnish) · 612/1,154,142 alleles

Filtering AF 0.0495% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0481%

Overall 0.0411% 642/1,562,322 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.053%	1,886
Remaining individualsnot grpmax-eligible	0.0281%	3,562
African / African-American	0.00947%	10,564
Finnishnot grpmax-eligible	0.00685%	14,601
Admixed American	0.00379%	26,382

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.Pro7Leu
Coding: c.20C>T
MANE Select: NM_000126
dbSNP: rs557160401
Type: single nucleotide variant
Location: chr15:76311369 (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 p.Pro7= 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
ETFA p.Arg122Lys 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-pro7leu (accessed [today's date]).

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