Is ETFA p.Arg249Cys (c.745C>T) pathogenic?

ETFA p.Arg249Cys (c.745C>T) is classified Conflicting classifications of pathogenicity in ETFA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.9989); Very rare (popmax 0.000681%, nfe); Associated with Glutaric acidemia type 2A.

What condition is associated with ETFA p.Arg249Cys (c.745C>T)?

ETFA p.Arg249Cys (c.745C>T) is associated with Glutaric acidemia type 2A, multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Arg249Cys (c.745C>T) in the general population?

ETFA p.Arg249Cys (c.745C>T) is very rare (popmax 0.000681%, nfe) (gnomAD).

What do computational predictors say about ETFA p.Arg249Cys (c.745C>T)?

AlphaMissense predicts likely pathogenic (score 0.9989) — an in-silico prediction, not a clinical call.

ETFA p.Arg249Cys

c.745C>T · rs1353938548 · VCV1444491

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000681%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Glutaric acidemia type 2A

Computational evidence

Protein change
AlphaMissense	0.9989	likely pathogenic · top 2% in ETFA
REVEL	0.949	strongly pathogenic-leaning
SaProt	LLR -15.38	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 9.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · 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

Grpmax group 0.000681% European (non-Finnish) · 8/1,175,106 alleles

Filtering AF 0.000293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000619% 9/1,454,268 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,040
European (non-Finnish)grpmax	0.000681%	146,888

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg249Cys
Coding: c.745C>T
MANE Select: NM_000126
dbSNP: rs1353938548
Type: single nucleotide variant
Location: chr15:76274483 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 249: the 'domain ii' region; a binding site; an α-helix

Full ETFA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Glutaric acidemia type 2A

Also linked: multiple acyl-CoA dehydrogenase deficiency

Similar variants

ETFA p.Arg249His 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-arg249cys (accessed [today's date]).

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