Is EDA p.Pro228fs (c.681_697del) pathogenic?

EDA p.Pro228fs (c.681697del) is classified Pathogenic in EDA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-29). Absent from gnomAD; Associated with X-linked hypohidrotic ectodermal dysplasia.

What condition is associated with EDA p.Pro228fs (c.681_697del)?

EDA p.Pro228fs (c.681_697del) is associated with X-linked hypohidrotic ectodermal dysplasia (ClinVar).

How common is EDA p.Pro228fs (c.681_697del) in the general population?

EDA p.Pro228fs (c.681_697del) is absent from gnomAD (gnomAD).

How is Hypohidrotic ectodermal dysplasia inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

EDA p.Pro228fs

c.681_697del · rs1556098978 · VCV528354

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

X-linked hypohidrotic ectodermal dysplasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 4 of 8
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 4.4, phastCons 1
Region caveats
Repeat context	tandem	GGACCCCCTGGTCCTCCA simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: EDA
Protein: p.Pro228fs
Coding: c.681_697del
MANE Select: NM_001399
dbSNP: rs1556098978
Type: Deletion
Location: chrX:70028008 (GRCh38)
Structure: AlphaFold pLDDT 70.59 · 3 PDB
Residue 228: the collagen-like domain; a UniProt-annotated variant site (in xhed; uncertain significance); the 'disordered' region

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

Disease context

X-linked hypohidrotic ectodermal dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hypohidrotic ectodermal dysplasia (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

EDA p.Pro228= Likely benign ★ same residue
EDA p.202_204IPG[1] Pathogenic/Likely pathogenic ★★ same condition
EDA p.217_219PGP[1] Pathogenic ★★ same condition
EDA p.Ala166fs Pathogenic ★★ same condition
EDA p.Asn185_Pro196del Pathogenic ★★ same condition
EDA p.Gly85fs Pathogenic ★★ same condition
EDA p.Phe317fs Pathogenic ★★ same condition
EDA p.Pro199fs Pathogenic ★★ 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/eda-p-pro228fs (accessed [today's date]).

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