Is ETFA p.Ser21Arg (c.63T>G) pathogenic?

ETFA p.Ser21Arg (c.63T>G) is classified Uncertain significance in ETFA (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-16). AlphaMissense: likely pathogenic (0.7463); Absent from gnomAD v4.1; Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA p.Ser21Arg (c.63T>G)?

ETFA p.Ser21Arg (c.63T>G) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Ser21Arg (c.63T>G) in the general population?

ETFA p.Ser21Arg (c.63T>G) is absent from gnomAD v4.1 (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.Ser21Arg (c.63T>G)?

AlphaMissense predicts likely pathogenic (score 0.7463) — an in-silico prediction, not a clinical call.

ETFA p.Ser21Arg

c.63T>G · rs1596224387 · VCV665820

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7463 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.7463	likely pathogenic
REVEL	0.43	indeterminate
SaProt	LLR -9.65	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -1, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	23.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ETFA
Protein: p.Ser21Arg
Coding: c.63T>G
MANE Select: NM_000126
dbSNP: rs1596224387
Type: single nucleotide variant
Location: chr15:76295714 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 21: 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

MADD p.Arg21Gly 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
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-ser21arg (accessed [today's date]).

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