Is ETFA p.Asn259Ser (c.776A>G) pathogenic?

ETFA p.Asn259Ser (c.776A>G) is classified Uncertain significance in ETFA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-18). AlphaMissense: ambiguous (0.3734); Very rare (popmax 0.0011%, sas).

How common is ETFA p.Asn259Ser (c.776A>G) in the general population?

ETFA p.Asn259Ser (c.776A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about ETFA p.Asn259Ser (c.776A>G)?

AlphaMissense predicts ambiguous (score 0.3734) — an in-silico prediction, not a clinical call.

ETFA p.Asn259Ser

c.776A>G · rs897415970 · VCV1712210

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3734 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3734	ambiguous
REVEL	0.73	pathogenic-leaning
SaProt	LLR -13.88	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 95 kb · p 0.0051 · regional, not allelic
Overall
CADD	26.2	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 0.0011% South Asian · 1/90,770 alleles

Overall 6.85e-05% 1/1,460,514 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.Asn259Ser
Coding: c.776A>G
MANE Select: NM_000126
dbSNP: rs897415970
Type: single nucleotide variant
Location: chr15:76274452 (GRCh38)
Gene constraint: LOEUF 1.166 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 94.00 · 4 PDB
Residue 259: the 'domain ii' region; an α-helix

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

Similar variants

ETFA p.Asn259Asp Uncertain significance ★ ⚠ same residue
ETFA c.186+1G>A Likely pathogenic ★★ same type
ETFA c.39+1G>A Likely pathogenic ★★ same type
ETFA c.451+1G>A Likely pathogenic ★★ same type
ETFA c.452-2A>G Likely pathogenic ★★ same type
ETFA c.664+1G>A Likely pathogenic ★★ same type
ETFA c.665-1G>A Likely pathogenic ★★ same type
ETFA p.Arg122Lys Likely pathogenic ★★ same type

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-asn259ser (accessed [today's date]).

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