Is ETFDH p.Arg99Pro (c.296G>C) pathogenic?

ETFDH p.Arg99Pro (c.296G>C) is classified Likely pathogenic in ETFDH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-01-17). AlphaMissense: likely pathogenic (0.9194); Absent from gnomAD v4.1; Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFDH p.Arg99Pro (c.296G>C)?

ETFDH p.Arg99Pro (c.296G>C) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFDH p.Arg99Pro (c.296G>C) in the general population?

ETFDH p.Arg99Pro (c.296G>C) 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 ETFDH p.Arg99Pro (c.296G>C)?

AlphaMissense predicts likely pathogenic (score 0.9194) — an in-silico prediction, not a clinical call.

ETFDH p.Arg99Pro

c.296G>C · rs376630579 · VCV1512149

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9194 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.9194	likely pathogenic ✓ concordant with ClinVar
REVEL	0.87	moderately pathogenic-leaning
SaProt	LLR -16.05	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 27 kb · p 0.78 · regional, not allelic
Overall
CADD	33.0	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: ETFDH
Protein: p.Arg99Pro
Coding: c.296G>C
MANE Select: NM_004453
dbSNP: rs376630579
Type: single nucleotide variant
Location: chr4:158682315 (GRCh38)
Gene constraint: LOEUF 1.126 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.60

Full ETFDH 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

ETFDH p.Arg99Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
ETFDH p.Arg99His Conflicting classifications of pathogenicity ★ ⚠ same residue
ETFDH c.1116+2T>C Likely pathogenic ★★ same condition
ETFDH c.1117-1G>A Likely pathogenic ★★ same condition
ETFDH c.1117-2A>G Pathogenic/Likely pathogenic ★★ same condition
ETFDH c.1285+1G>A Pathogenic ★★ same condition
ETFDH c.1469-1G>T Likely pathogenic ★★ same condition
ETFDH c.1690+1G>T 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/etfdh-p-arg99pro (accessed [today's date]).

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