# NM_001399.5(EDA):c.913A>C (p.Ser305Arg)

https://sugi.bio/variant/eda-p-ser305arg

## Summary

**EDA p.Ser305Arg (c.913A>C)** is classified **Likely pathogenic** in EDA (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-19). AlphaMissense: likely pathogenic (0.9999); Absent from gnomAD v4.1; Associated with X-linked hypohidrotic ectodermal dysplasia.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EDA gene that is considered likely disease-causing, 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/) |
| Protein change (HGVS p.) | p.Ser305Arg |
| Coding change (HGVS c.) | c.913A>C |
| MANE Select transcript | [NM_001399](https://www.ncbi.nlm.nih.gov/nuccore/NM_001399) |
| Variant type | single nucleotide variant |
| Location | chrX:70033517-70033517 (GRCh38) |
| ClinVar | [VCV4746380](https://www.ncbi.nlm.nih.gov/clinvar/variation/4746380/) |

**All HGVS expressions:** `NC_000023.10:g.69253367A>C`, `NC_000023.11:g.70033517A>C`, `NG_009809.2:g.422451A>C`, `NM_001005609.2:c.913A>C`, `NM_001005612.3:c.904A>C`, `NM_001399.5:c.913A>C`, `NM_001440761.1:c.904A>C`, `NM_001440762.1:c.882+31A>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9999) — concordant with the pathogenic call
- REVEL 0.951 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.068 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.303, GERP 4.83, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 2%** most-pathogenic-predicted substitutions in EDA (of 2,276 modeled).
- CADD: **PHRED 33.0**. 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.*
- Regional missense constraint: **o/e 0.62** across the covering region of the MANE Select transcript (69,616,455–70,035,606), spanning 419,151 bp. Chi-square p 2e-10. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}

Residue **305** lies in a β-strand; the thd domain.

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. p.Ser305Arg falls in the thd domain.


### 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}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-19.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-04-19 |

## 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, Anhidrotic ectodermal dysplasia X-linked, Christ Siemens Touraine syndrome, ECTODERMAL DYSPLASIA 1, HYPOHIDROTIC, X-LINKED, ECTODERMAL DYSPLASIA 1, HYPOHIDROTIC/HAIR/TOOTH TYPE, X-LINKED, ECTODERMAL DYSPLASIA 1, Christ-Siemans-Touraine syndrome, Ectodermal Dysplasia 1, Anhidrotic.

## Same-residue context {#hotspot}

Residue **305** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [EDA p.Ser305fs](/variant/eda-p-ser305fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related EDA variant pages (same residue, condition, or type): [EDA p.Ser305Asn](/variant/eda-p-ser305asn), [EDA p.Ser305fs](/variant/eda-p-ser305fs), [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).

### 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 4746380). 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.*