# NM_006579.3(EBP):c.558G>A (p.Trp186Ter)

https://sugi.bio/variant/ebp-p-trp186ter

## Summary

**EBP p.Trp186Ter (c.558G>A)** is classified **Pathogenic** in EBP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-19). Absent from gnomAD v4.1; Associated with X-linked chondrodysplasia punctata 2.

**At a glance:** Pathogenic · review: Multiple submitters · 2 submitters · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the EBP gene that is considered disease-causing, submitted by 2 submitters, 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.Trp186Ter |
| Coding change (HGVS c.) | c.558G>A |
| MANE Select transcript | [NM_006579](https://www.ncbi.nlm.nih.gov/nuccore/NM_006579) |
| Variant type | single nucleotide variant |
| Location | chrX:48528322-48528322 (GRCh38) |
| ClinVar | [VCV4710748](https://www.ncbi.nlm.nih.gov/clinvar/variation/4710748/) |

**All HGVS expressions:** `NC_000023.10:g.48386710G>A`, `NC_000023.11:g.48528322G>A`, `NG_007452.1:g.11547G>A`, `NM_006579.3:c.558G>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 (below), not from a missing predictor score.
- Conservation: phyloP 11.62, GERP 2.09, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — 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.*
- CADD: **PHRED 37.0**. 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.*
- 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 3/3, triplosensitivity 0/3. *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 **186** 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.Trp186Ter 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-12-19.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-19 |
| Variantyx, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2025-09-05 |

## 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, not provided, EBP-Related X-Linked Chondrodysplasia Punctata, CONRADI-HUNERMANN-HAPPLE SYNDROME, HAPPLE SYNDROME, Hunermann-Conradi Syndrome, none provided.

## Similar variants {#similar}

Related EBP variant pages (same residue, condition, or type): [EBP p.Trp186Arg](/variant/ebp-p-trp186arg), [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.Trp61Ter](/variant/ebp-p-trp61ter).

### 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 2026-10-14); 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 4710748). 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.*