Is ETFA p.Pro258Ala (c.772C>G) pathogenic?

ETFA p.Pro258Ala (c.772C>G) is classified Uncertain significance in ETFA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.1938); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with ETFA p.Pro258Ala (c.772C>G)?

ETFA p.Pro258Ala (c.772C>G) is associated with Inborn genetic diseases (ClinVar).

How common is ETFA p.Pro258Ala (c.772C>G) in the general population?

ETFA p.Pro258Ala (c.772C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ETFA p.Pro258Ala (c.772C>G)?

AlphaMissense predicts likely benign (score 0.1938) — an in-silico prediction, not a clinical call.

ETFA p.Pro258Ala

c.772C>G · VCV4251290

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1938 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1938	likely benign
REVEL	0.586	indeterminate
SaProt	LLR -8.65	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 8.5	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	24.0	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

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.Pro258Ala
Coding: c.772C>G
MANE Select: NM_000126
Type: single nucleotide variant
Location: chr15:76274456 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 258: 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.Pro258= Conflicting classifications of pathogenicity ★ 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
ETFA p.Gly72Asp 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-pro258ala (accessed [today's date]).

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