# NM_001399.5(EDA):c.953C>A (p.Ala318Asp)

https://sugi.bio/variant/eda-p-ala318asp

## Summary

**EDA p.Ala318Asp (c.953C>A)** is classified **Likely pathogenic** in EDA (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-08). AlphaMissense: likely pathogenic (0.9996); Absent from gnomAD v4.1.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs2147518971 · 1 submitter · 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.

*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.*

**Support & next steps:** [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.Ala318Asp |
| Coding change (HGVS c.) | c.953C>A |
| MANE Select transcript | [NM_001399](https://www.ncbi.nlm.nih.gov/nuccore/NM_001399) |
| dbSNP | [rs2147518971](https://www.ncbi.nlm.nih.gov/snp/rs2147518971/) |
| Variant type | single nucleotide variant |
| Location | chrX:70035386-70035386 (GRCh38) |
| ClinVar | [VCV1206951](https://www.ncbi.nlm.nih.gov/clinvar/variation/1206951/) |

**All HGVS expressions:** `NC_000023.10:g.69255236C>A`, `NC_000023.11:g.70035386C>A`, `NG_009809.2:g.424320C>A`, `NM_001005609.2:c.947C>A`, `NM_001005612.3:c.938C>A`, `NM_001399.5:c.953C>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9996) — concordant with the pathogenic call
- REVEL 0.833 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.331 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- SpliceAI predicts **acceptor gain** (Δ 0.21) — consistent with the pathogenic call
- Conservation: phyloP 7.532, GERP 4.68, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 2%** most-pathogenic-predicted substitutions in EDA (of 2,276 modeled).
- CADD: **PHRED 32.0**. 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 deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.21**, donor gain **0.00**.
- 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 **318** 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.Ala318Asp 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 2020-04-08.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-04-08 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related EDA variant pages (same residue, condition, or type): [EDA c.526+2T>C](/variant/eda-c-526-plus-2t-c), [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).

### 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 1206951). 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.*