Is ETFA p.Arg122Lys (c.365G>A) pathogenic?

ETFA p.Arg122Lys (c.365G>A) is classified Likely pathogenic in ETFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-04). AlphaMissense: likely pathogenic (0.74); Very rare (popmax 0.00892%, eas); Associated with Glutaric acidemia type 2A.

What condition is associated with ETFA p.Arg122Lys (c.365G>A)?

ETFA p.Arg122Lys (c.365G>A) is associated with Glutaric acidemia type 2A, multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Arg122Lys (c.365G>A) in the general population?

ETFA p.Arg122Lys (c.365G>A) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about ETFA p.Arg122Lys (c.365G>A)?

AlphaMissense predicts likely pathogenic (score 0.74) — an in-silico prediction, not a clinical call.

ETFA p.Arg122Lys

c.365G>A · rs773865838 · VCV2675076

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.74 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Glutaric acidemia type 2A

Computational evidence

Protein change
AlphaMissense	0.74	likely pathogenic ✓ concordant with ClinVar
REVEL	0.921	moderately pathogenic-leaning
SaProt	LLR -11.30	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 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	27.7	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 0.00892% East Asian · 4/44,866 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000372% 6/1,613,740 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,216
European (non-Finnish)	0.00017%	589,897

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.Arg122Lys
Coding: c.365G>A
MANE Select: NM_000126
dbSNP: rs773865838
Type: single nucleotide variant
Location: chr15:76287932 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 122: the 'domain i' region; 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.Arg122= Conflicting classifications of pathogenicity ★ 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.Arg18Ter Pathogenic/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-arg122lys (accessed [today's date]).

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