# NM_006579.3(EBP):c.278A>T (p.Asp93Val)

https://sugi.bio/variant/ebp-p-asp93val

## Summary

**EBP p.Asp93Val (c.278A>T)** is classified **Likely pathogenic** in EBP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-29). AlphaMissense: likely pathogenic (0.7344); Absent from gnomAD v4.1; Associated with X-linked chondrodysplasia punctata 2.

**At a glance:** Likely pathogenic · review: Single submitter · rsID rs1569479610 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EBP gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to X-linked chondrodysplasia punctata 2.

*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) | X-linked dominant |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |

**Commonly reported features of X-linked dominant chondrodysplasia punctata** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the skin — Very frequent (99-80%)
- Epiphyseal stippling — Very frequent (99-80%)
- Facial asymmetry — Frequent (79-30%)
- Cataract — Frequent (79-30%)
- Abnormal skull morphology — Frequent (79-30%)
- Erythroderma — Frequent (79-30%)
- Frontal bossing — Frequent (79-30%)
- Short stature — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0006189/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EBP](https://sugi.bio/atlas/gene/EBP/) |
| Protein change (HGVS p.) | p.Asp93Val |
| Coding change (HGVS c.) | c.278A>T |
| MANE Select transcript | [NM_001378122](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378122) (variant reported on NM_006579) |
| dbSNP | [rs1569479610](https://www.ncbi.nlm.nih.gov/snp/rs1569479610/) |
| Variant type | single nucleotide variant |
| Location | chrX:48524049-48524049 (GRCh38) |
| ClinVar | [VCV2498139](https://www.ncbi.nlm.nih.gov/clinvar/variation/2498139/) |

**All HGVS expressions:** `NC_000023.10:g.48382437A>T`, `NC_000023.11:g.48524049A>T`, `NG_007452.1:g.7274A>T`, `NM_006579.3:c.278A>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.7344) — concordant with the pathogenic call
- REVEL 0.868 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -10.49 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.065, GERP 2.04, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in EBP (of 4,616 modeled).
- CADD: **PHRED 25.6**. 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.*
- 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}

**EBP** 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.*

Curated gene–disease validity (ClinGen):

- **MEND syndrome** — Definitive (XL)

## Protein context {#protein}

Residue **93** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 59.09, 10% of residues very-high.

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

*Describes the biological roles of EBP (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:** EBP's established molecular role includes proline-rich region binding. p.Asp93Val falls in the disordered region.


### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Golgi Associated Vesicle Biogenesis](https://reactome.org/content/detail/R-HSA-432722) | curated |

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

**Molecular function:** proline-rich region binding.

**Biological process:** positive regulation of membrane protein ectodomain proteolysis.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-06-29.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-06-29 |

## Associated conditions {#conditions}

[X-linked chondrodysplasia punctata 2](https://sugi.bio/atlas/disease/x-linked-chondrodysplasia-punctata-2/).

**Reported phenotype names (ClinVar):** Chondrodysplasia punctata 2 X-linked dominant, CONRADI-HUNERMANN-HAPPLE SYNDROME, HAPPLE SYNDROME, EBP-Related X-Linked Chondrodysplasia Punctata, Hunermann-Conradi Syndrome.

## Similar variants {#similar}

Related EBP variant pages (same residue, condition, or type): [EBP p.Asp93Gly](/variant/ebp-p-asp93gly), [EBP p.Arg110Gln](/variant/ebp-p-arg110gln), [EBP p.Arg110Ter](/variant/ebp-p-arg110ter), [EBP p.Arg147His](/variant/ebp-p-arg147his), [EBP p.Arg62Trp](/variant/ebp-p-arg62trp), [EBP p.Glu80Lys](/variant/ebp-p-glu80lys), [EBP p.Gly161Arg](/variant/ebp-p-gly161arg), [EBP p.Trp186Ter](/variant/ebp-p-trp186ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2498139). 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.*