Is ETFA p.Val323Ile (c.967G>A) pathogenic?

ETFA p.Val323Ile (c.967G>A) is classified Uncertain significance in ETFA (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.1361); Very rare (popmax 0.00167%, amr); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA p.Val323Ile (c.967G>A)?

ETFA p.Val323Ile (c.967G>A) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Val323Ile (c.967G>A) in the general population?

ETFA p.Val323Ile (c.967G>A) is very rare (popmax 0.00167%, amr) (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.Val323Ile (c.967G>A)?

AlphaMissense predicts likely benign (score 0.1361) — an in-silico prediction, not a clinical call.

ETFA p.Val323Ile

c.967G>A · rs1225887341 · VCV849799

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.1361	likely benign
REVEL	0.358	indeterminate
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.38	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	21.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00167% Admixed American · 1/59,954 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000252% 4/1,587,258 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,954
European (non-Finnish)	0.00026%	385,229

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.Val323Ile
Coding: c.967G>A
MANE Select: NM_000126
dbSNP: rs1225887341
Type: single nucleotide variant
Location: chr15:76216594 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 323: the 'domain ii' region; an α-helix

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

ETFA c.186+1G>A Likely pathogenic ★★ same condition
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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
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-val323ile (accessed [today's date]).

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