# NM_006579.3(EBP):c.188G>A (p.Arg63Gln)

https://sugi.bio/variant/ebp-p-arg63gln

## Summary

**EBP p.Arg63Gln (c.188G>A)** is classified **Conflicting classifications of pathogenicity** in EBP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-01-22). AlphaMissense: likely benign (0.1339); Very rare (popmax 0.00927%, nfe); Associated with X-linked chondrodysplasia punctata 2.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs782638360 · 5 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00927%, nfe)

## For patients & families {#patients}

This is a change in the EBP gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 5 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.Arg63Gln |
| Coding change (HGVS c.) | c.188G>A |
| MANE Select transcript | [NM_006579](https://www.ncbi.nlm.nih.gov/nuccore/NM_006579) |
| dbSNP | [rs782638360](https://www.ncbi.nlm.nih.gov/snp/rs782638360/) |
| Variant type | single nucleotide variant |
| Location | chrX:48523959-48523959 (GRCh38) |
| ClinVar | [VCV811902](https://www.ncbi.nlm.nih.gov/clinvar/variation/811902/) |

**All HGVS expressions:** `NC_000023.10:g.48382347G>A`, `NC_000023.11:g.48523959G>A`, `NG_007452.1:g.7184G>A`, `NM_006579.3:c.188G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1339)
- REVEL 0.804 (moderately pathogenic-leaning) — differs from AlphaMissense
- SaProt LLR -10.201 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** REVEL and SaProt call this damaging; AlphaMissense does not
- SpliceAI predicts **acceptor gain** (Δ 0.24) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 8.447, GERP 1.03, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 29.2**. 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 deltas (raw): acceptor loss **0.07**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.07**, donor loss **0.00**, acceptor gain **0.24**, donor gain **0.00**.
- Pangolin: Δ**0.21** (gain), gain 0.21 / loss 0.00. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00927%** (nfe) · FAF95 0.00764% · FAF99 0.00702% · 83/895,063 in the highest group · 89/1,209,167 alleles overall — very rare (popmax 0.00927%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0126% | 7,931 |
| European (non-Finnish) (grpmax) | 0.00927% | 10,784 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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 **63** 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.Arg63Gln 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-01-22.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Benign, 1 Likely benign).

**Submission history:** 5 submissions (2019–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-02-24 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-27 |
| Breakthrough Genomics, Breakthrough Genomics | Uncertain significance | criteria provided, single submitter | not provided |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-01-22 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Chondrodysplasia punctata 2 X-linked dominant, not specified, MEND syndrome, not provided, HAPPLE SYNDROME, CONRADI-HUNERMANN-HAPPLE SYNDROME, EBP-Related X-Linked Chondrodysplasia Punctata, Hunermann-Conradi Syndrome, MALE EBP DISORDER WITH NEUROLOGIC DEFECTS, none provided.

## Same-residue context {#hotspot}

Residue **63** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [EBP p.Arg63Ter](/variant/ebp-p-arg63ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related EBP variant pages (same residue, condition, or type): [EBP p.Arg63Ter](/variant/ebp-p-arg63ter), [EBP p.Arg110Gln](/variant/ebp-p-arg110gln), [EBP p.Arg110Ter](/variant/ebp-p-arg110ter), [EBP p.Arg147Cys](/variant/ebp-p-arg147cys), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 811902). 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.*