Is ETFA p.Val165Ala (c.494T>C) pathogenic?

ETFA p.Val165Ala (c.494T>C) is classified Conflicting classifications of pathogenicity in ETFA (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-06-23). AlphaMissense: likely pathogenic (0.7447); Very rare (popmax 0.00891%, eas); Associated with multiple acyl-CoA dehydrogenase deficiency.

What condition is associated with ETFA p.Val165Ala (c.494T>C)?

ETFA p.Val165Ala (c.494T>C) is associated with multiple acyl-CoA dehydrogenase deficiency (ClinVar).

How common is ETFA p.Val165Ala (c.494T>C) in the general population?

ETFA p.Val165Ala (c.494T>C) is very rare (popmax 0.00891%, eas) (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.Val165Ala (c.494T>C)?

AlphaMissense predicts likely pathogenic (score 0.7447) — an in-silico prediction, not a clinical call.

ETFA p.Val165Ala

c.494T>C · rs749455172 · VCV1301310

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7447 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

multiple acyl-CoA dehydrogenase deficiency

Computational evidence

Protein change
AlphaMissense	0.7447	likely pathogenic
REVEL	0.905	moderately pathogenic-leaning
SaProt	LLR -11.74	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	27.4	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 0.00891% East Asian · 4/44,870 alleles

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

Overall 0.000682% 11/1,613,650 alleles · very rare exomes 11/1,461,342 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,218
European (non-Finnish)	0.000593%	168,511

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.Val165Ala
Coding: c.494T>C
MANE Select: NM_000126
dbSNP: rs749455172
Type: single nucleotide variant
Location: chr15:76286439 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 165: the 'domain i' region; a β-strand

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 p.Val165= Likely benign ★ same residue
MADD p.Ala165Val Uncertain significance ★★ ⚠ same residue
MADD p.Ala165Gly 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

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-val165ala (accessed [today's date]).

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