Is ETFA p.Arg46Cys (c.136C>T) pathogenic?

ETFA p.Arg46Cys (c.136C>T) is classified Uncertain significance in ETFA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-10). AlphaMissense: likely benign (0.1291); Very rare (popmax 0.00167%, amr); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA p.Arg46Cys (c.136C>T)?

ETFA p.Arg46Cys (c.136C>T) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Arg46Cys (c.136C>T) in the general population?

ETFA p.Arg46Cys (c.136C>T) is very rare (popmax 0.00167%, amr) (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.Arg46Cys (c.136C>T)?

AlphaMissense predicts likely benign (score 0.1291) — an in-silico prediction, not a clinical call.

ETFA p.Arg46Cys

c.136C>T · rs769908660 · VCV2158300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1291 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.1291	likely benign
REVEL	0.326	indeterminate
SaProt	LLR -11.57	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -1.5, phastCons 0.002
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	20.4	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 0.00167% Admixed American · 1/59,970 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000744% 12/1,613,420 alleles · very rare exomes 10/1,461,448 · genomes 2/151,972 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,970
Remaining individualsnot grpmax-eligible	0.0016%	62,466
African / African-American	0.00134%	74,842
European (non-Finnish)	0.000763%	131,069

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.Arg46Cys
Coding: c.136C>T
MANE Select: NM_000126
dbSNP: rs769908660
Type: single nucleotide variant
Location: chr15:76295641 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 46: the 'domain i' region; a turn

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.Arg46His Uncertain significance ★ ⚠ same residue
ETFA p.Arg46Leu 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-arg46cys (accessed [today's date]).

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