Is EDA p.Cys346Trp (c.1038C>G) pathogenic?

EDA p.Cys346Trp (c.1038C>G) is classified Likely pathogenic in EDA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-01). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1.

How common is EDA p.Cys346Trp (c.1038C>G) in the general population?

EDA p.Cys346Trp (c.1038C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about EDA p.Cys346Trp (c.1038C>G)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

EDA p.Cys346Trp

c.1038C>G · VCV3371229

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic ✓ concordant with ClinVar · top 2% in EDA
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -15.85	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 -0.014	GERP 0.43, phastCons 0.85
Regional constraint	o/e 0.62	unconstrained · MANE · 419 kb · p 2e-10 · regional, not allelic
Overall
CADD	24.4	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

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: EDA
Protein: p.Cys346Trp
Coding: c.1038C>G
MANE Select: NM_001399
Type: single nucleotide variant
Location: chrX:70035471 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 346: a UniProt-annotated variant site (in xhed); a β-strand; a disulfide bond; the thd domain

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

Similar variants

EDA p.Cys346Arg Likely pathogenic ★ same residue
EDA p.Cys346_Ala349del Uncertain significance ★ same residue
EDA c.526+2T>C Pathogenic/Likely pathogenic ★★ same type
EDA c.526+5G>T Likely pathogenic ★★ same type
EDA c.527-2A>G Pathogenic/Likely pathogenic ★★ same type
EDA c.706+1G>A Pathogenic/Likely pathogenic ★★ same type
EDA c.707-13T>G Pathogenic ★★ same type
EDA c.742-2A>G Pathogenic/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/eda-p-cys346trp (accessed [today's date]).

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