# NM_001399.5(EDA):c.396+1G>A

https://sugi.bio/variant/eda-c-396-plus-1g-a

## Summary

**EDA c.396+1G>A** is classified **Pathogenic** in EDA (ClinVar, Single submitter, 1 submitter; last evaluated 2013-04-11). Absent from gnomAD v4.1; Associated with X-linked hypohidrotic ectodermal dysplasia.

**At a glance:** Pathogenic · review: Single submitter · rsID rs727504537 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EDA gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to X-linked hypohidrotic ectodermal dysplasia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Autosomal recessive, X-linked recessive |
| Age of onset (of this condition) | Infancy, Neonatal |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 14 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | EDA is a diagnostic-grade gene on 4 Genomics England panels |

**Commonly reported features of Hypohidrotic ectodermal dysplasia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the dentition — Very frequent (99-80%)
- Hypoplasia of the maxilla — Very frequent (99-80%)
- Dry skin — Very frequent (99-80%)
- Thin skin — Very frequent (99-80%)
- Keratoconjunctivitis sicca — Very frequent (99-80%)
- Abnormal facial shape — Very frequent (99-80%)
- Abnormal dental morphology — Very frequent (99-80%)
- Irregular hyperpigmentation — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010427/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EDA](https://sugi.bio/atlas/gene/EDA/) |
| Coding change (HGVS c.) | c.396+1G>A |
| MANE Select transcript | [NM_001399](https://www.ncbi.nlm.nih.gov/nuccore/NM_001399) |
| dbSNP | [rs727504537](https://www.ncbi.nlm.nih.gov/snp/rs727504537/) |
| Variant type | single nucleotide variant |
| Location | chrX:69616705-69616705 (GRCh38) |
| ClinVar | [VCV178916](https://www.ncbi.nlm.nih.gov/clinvar/variation/178916/) |

**All HGVS expressions:** `NC_000023.10:g.68836549G>A`, `NC_000023.11:g.69616705G>A`, `NG_009809.2:g.5639G>A`, `NM_001005609.2:c.396+1G>A`, `NM_001005610.4:c.396+1G>A`, `NM_001005612.3:c.396+1G>A`, `NM_001005613.4:c.396+1G>A`, `NM_001005615.1:c.397G>A`, `NM_001399.5:c.396+1G>A`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.99) — consistent with the pathogenic call
- Conservation: phyloP 8.064, GERP 1.37, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **canonical splice-site (±1/±2)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- CADD: **PHRED 29.7**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Splice region: **canonical splice dinucleotide (donor +1)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **not assessed** — the gnomAD non-coding genomic-constraint release is computed on the autosomes only, so chrX has no window. That is a property of the dataset, not of the variant: it is not evidence that the region is unconstrained.
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.99**, acceptor gain **0.00**, donor gain **0.46**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.99**, acceptor gain **0.00**, donor gain **0.46**.
- Pangolin: Δ**0.83** (loss), gain 0.13 / loss 0.83. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**EDA** population constraint: ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 70.59, 38% of residues very-high.

**3 experimental structure(s)** (PDB): [1RJ7](https://www.rcsb.org/structure/1RJ7), [1RJ8](https://www.rcsb.org/structure/1RJ8), [7X9G](https://www.rcsb.org/structure/7X9G).

## What this gene does {#gene-function}

*Describes the biological roles of EDA (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** EDA's established molecular role includes signaling receptor binding.


### Pathways affected {#pathways}

EDA participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [TNFs bind their physiological receptors](https://reactome.org/content/detail/R-HSA-5669034) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** signaling receptor binding, death receptor binding, cytokine activity, death receptor agonist activity.

**Biological process:** cytokine-mediated signaling pathway, odontogenesis of dentin-containing tooth, positive regulation of canonical NF-kappaB signal transduction, regulation of non-canonical NF-kappaB signal transduction.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2013-04-11.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Pathogenic | criteria provided, single submitter | clinical testing | 2013-04-11 |

## Associated conditions {#conditions}

[X-linked hypohidrotic ectodermal dysplasia](https://sugi.bio/atlas/disease/x-linked-hypohidrotic-ectodermal-dysplasia/).

**Reported phenotype names (ClinVar):** Hypohidrotic X-linked ectodermal dysplasia, ECTODERMAL DYSPLASIA, HYPOHIDROTIC, 1, CST SYNDROME, ECTODERMAL DYSPLASIA 1, Ectodermal Dysplasia 1, Anhidrotic, Anhidrotic ectodermal dysplasia X-linked, Christ Siemens Touraine syndrome, ECTODERMAL DYSPLASIA 1, HYPOHIDROTIC, X-LINKED, ECTODERMAL DYSPLASIA 1, HYPOHIDROTIC/HAIR/TOOTH TYPE, X-LINKED, Christ-Siemans-Touraine syndrome.

## Similar variants {#similar}

Related EDA variant pages (same residue, condition, or type): [EDA c.526+5G>T](/variant/eda-c-526-plus-5g-t), [EDA c.527-2A>G](/variant/eda-c-527-minus-2a-g), [EDA c.706+1G>A](/variant/eda-c-706-plus-1g-a), [EDA c.707-13T>G](/variant/eda-c-707-minus-13t-g), [EDA c.742-2A>G](/variant/eda-c-742-minus-2a-g), [EDA c.924+1G>T](/variant/eda-c-924-plus-1g-t), [EDA p.Ala349Ser](/variant/eda-p-ala349ser), [EDA p.Ala349Thr](/variant/eda-p-ala349thr).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 178916). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*