Is ETFA p.Val217Leu (c.649G>C) pathogenic?

ETFA p.Val217Leu (c.649G>C) is classified Uncertain significance in ETFA (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-02-03). AlphaMissense: likely pathogenic (0.5835); Absent from gnomAD v4.1; Associated with Glutaric acidemia type 2A.

What condition is associated with ETFA p.Val217Leu (c.649G>C)?

ETFA p.Val217Leu (c.649G>C) is associated with Glutaric acidemia type 2A (ClinVar).

How common is ETFA p.Val217Leu (c.649G>C) in the general population?

ETFA p.Val217Leu (c.649G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ETFA p.Val217Leu (c.649G>C)?

AlphaMissense predicts likely pathogenic (score 0.5835) — an in-silico prediction, not a clinical call.

ETFA p.Val217Leu

c.649G>C · VCV4067431

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5835 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Glutaric acidemia type 2A

Computational evidence

Protein change
AlphaMissense	0.5835	likely pathogenic
REVEL	0.661	pathogenic-leaning
SaProt	LLR -10.08	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 4.8	GERP 0.65, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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.Val217Leu
Coding: c.649G>C
MANE Select: NM_000126
Type: single nucleotide variant
Location: chr15:76285652 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 217: the 'domain ii' region; a β-strand

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

Disease context

Glutaric acidemia type 2A

Similar variants

MADD p.Gly217Asp Benign ★★ same residue
ETFA p.Arg122Lys Likely pathogenic ★★ same condition
ETFA p.Arg18Ter Pathogenic/Likely pathogenic ★★ same condition
ETFA p.Arg209Ter Pathogenic/Likely pathogenic ★★ same condition
ETFA p.Arg223Ter Pathogenic/Likely pathogenic ★★ same condition
ETFA p.Gln65Ter Likely pathogenic ★★ same condition
ETFA p.Gly116Arg Likely pathogenic ★★ same condition
ETFA p.Met1Ile 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-val217leu (accessed [today's date]).

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