Is ETFA p.Ala305Val (c.914C>T) pathogenic?

ETFA p.Ala305Val (c.914C>T) is classified Uncertain significance in ETFA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-03). AlphaMissense: likely pathogenic (0.9863); Very rare (popmax 0.000255%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ETFA p.Ala305Val (c.914C>T)?

ETFA p.Ala305Val (c.914C>T) is associated with Inborn genetic diseases (ClinVar).

How common is ETFA p.Ala305Val (c.914C>T) in the general population?

ETFA p.Ala305Val (c.914C>T) is very rare (popmax 0.000255%, nfe) (gnomAD).

What do computational predictors say about ETFA p.Ala305Val (c.914C>T)?

AlphaMissense predicts likely pathogenic (score 0.9863) — an in-silico prediction, not a clinical call.

ETFA p.Ala305Val

c.914C>T · rs2542963617 · VCV2280352

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000255%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9863	likely pathogenic
REVEL	0.944	strongly pathogenic-leaning
SaProt	LLR -12.62	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 12	GERP 0.68, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.000255% European (non-Finnish) · 3/1,177,980 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000206% 3/1,459,510 alleles · very rare

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.Ala305Val
Coding: c.914C>T
MANE Select: NM_000126
dbSNP: rs2542963617
Type: single nucleotide variant
Location: chr15:76225898 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 305: the 'domain ii' 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

MADD p.Gly305Val Pathogenic same residue
ETFA p.Ala305Thr Uncertain significance ⚠ same residue
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

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-ala305val (accessed [today's date]).

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