# NM_006579.3(EBP):c.159del (p.Ala54fs)

https://sugi.bio/variant/ebp-p-ala54fs

## Summary

**EBP p.Ala54fs (c.159del)** is classified **Likely pathogenic** in EBP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-12). Associated with X-linked chondrodysplasia punctata 2.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## 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.Ala54fs |
| Coding change (HGVS c.) | c.159del |
| MANE Select transcript | [NM_001378122](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378122) (variant reported on NM_006579) |
| Variant type | Deletion |
| Location | chrX:48523930-48523930 (GRCh38) |
| ClinVar | [VCV4293428](https://www.ncbi.nlm.nih.gov/clinvar/variation/4293428/) |

**All HGVS expressions:** `NC_000023.10:g.48382318del`, `NC_000023.11:g.48523930del`, `NG_007452.1:g.7155del`, `NM_006579.3:c.159del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 (below), not from a missing predictor score.
- Conservation: phyloP -0.242, GERP 2.04, phastCons 0.056 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. For a truncating variant the loss-of-function impact is position-dependent — C-terminal / last-exon truncations may escape nonsense-mediated decay. *Descriptive; not an applied PVS1 code.*
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 **54** 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.Ala54fs 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 2024-08-12.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| 3billion | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-08-12 |

## 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, Hunermann-Conradi Syndrome, EBP-Related X-Linked Chondrodysplasia Punctata, CONRADI-HUNERMANN-HAPPLE SYNDROME, HAPPLE SYNDROME.

## Similar variants {#similar}

Related EBP variant pages (same residue, condition, or type): [EBP p.Ala54Val](/variant/ebp-p-ala54val), [EBP p.Ser98fs](/variant/ebp-p-ser98fs), [EBP p.Ala54=](/variant/ebp-p-ala54), [EBP p.Pro131fs](/variant/ebp-p-pro131fs), [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).

### 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 4293428). 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.*