Is ETFA p.Val194Met (c.580G>A) pathogenic?

ETFA p.Val194Met (c.580G>A) is classified Conflicting classifications of pathogenicity in ETFA (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-08-26). AlphaMissense: likely benign (0.1339); Ultra-rare (popmax 0.0165%, mid); Associated with Inborn genetic diseases.

What condition is associated with ETFA p.Val194Met (c.580G>A)?

ETFA p.Val194Met (c.580G>A) is associated with Inborn genetic diseases (ClinVar).

How common is ETFA p.Val194Met (c.580G>A) in the general population?

ETFA p.Val194Met (c.580G>A) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about ETFA p.Val194Met (c.580G>A)?

AlphaMissense predicts likely benign (score 0.1339) — an in-silico prediction, not a clinical call.

ETFA p.Val194Met

c.580G>A · rs753363278 · VCV203688

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1339 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1339	likely benign
REVEL	0.351	indeterminate
SaProt	LLR -6.50	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.6, phastCons 0.99
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	22.4	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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00131% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00162% 26/1,605,464 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
European (non-Finnish)	0.00196%	50,970
Remaining individualsnot grpmax-eligible	0.00161%	62,174
African / African-American	0.00134%	74,738

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.Val194Met
Coding: c.580G>A
MANE Select: NM_000126
dbSNP: rs753363278
Type: single nucleotide variant
Location: chr15:76285721 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 194: the 'domain i' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ETFA p.Arg169Cys Uncertain significance ★★ ⚠ same condition
ETFA p.Arg249His Uncertain significance ★★ ⚠ same condition
ETFA p.Asp174Gly Uncertain significance ★★ ⚠ same condition
ETFA p.Gln9Arg Uncertain significance ★★ ⚠ same condition
ETFA p.Glu186Gly Uncertain significance ★★ ⚠ same condition
ETFA p.Gly181Ser Uncertain significance ★★ ⚠ same condition
ETFA p.Gly72Asp Uncertain significance ★★ ⚠ same condition
ETFA p.Leu88Pro Uncertain significance ★★ ⚠ 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-val194met (accessed [today's date]).

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