# NM_006579.3(EBP):c.414C>T (p.Ile138=)

https://sugi.bio/variant/ebp-p-ile138

## Summary

**EBP p.Ile138= (c.414C>T)** is classified **Conflicting classifications of pathogenicity** in EBP (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-18). Very rare (popmax 0.00218%, amr); Associated with MEND syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs976210101 · 3 submitters · 2 linked conditions · very rare (popmax 0.00218%, amr)

## 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 3 submitters, and is linked to MEND syndrome.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017666/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.Ile138= |
| Coding change (HGVS c.) | c.414C>T |
| MANE Select transcript | [NM_001378122](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378122) (variant reported on NM_006579) |
| dbSNP | [rs976210101](https://www.ncbi.nlm.nih.gov/snp/rs976210101/) |
| Variant type | single nucleotide variant |
| Location | chrX:48527230-48527230 (GRCh38) |
| ClinVar | [VCV759959](https://www.ncbi.nlm.nih.gov/clinvar/variation/759959/) |

**All HGVS expressions:** `NC_000023.10:g.48385618C>T`, `NC_000023.11:g.48527230C>T`, `NG_007452.1:g.10455C>T`, `NM_006579.3:c.414C>T`

## 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 -5.407, GERP -4.15 — fast-evolving / accelerated position
- CADD: **PHRED 1.176**. 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 (gnomAD v4.1): grpmax **0.00218%** (amr) · FAF95 0.000325% · FAF99 0.000209% · 1/45,975 in the highest group · 9/1,098,195 alleles overall — very rare (popmax 0.00218%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00218% | 45,975 |
| African / African-American | 0.00174% | 57,629 |
| European (non-Finnish) | 0.000782% | 127,914 |

*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 **138** 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.Ile138= 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 2025-08-18.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-19 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-18 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-11 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** MEND syndrome, not provided, Chondrodysplasia punctata 2 X-linked dominant, not specified, MALE EBP DISORDER WITH NEUROLOGIC DEFECTS, CONRADI-HUNERMANN-HAPPLE SYNDROME, HAPPLE SYNDROME, Hunermann-Conradi Syndrome, EBP-Related X-Linked Chondrodysplasia Punctata, AllHighlyPenetrant.

## Similar variants {#similar}

Related EBP variant pages (same residue, condition, or type): [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), [EBP p.Trp186Ter](/variant/ebp-p-trp186ter).

### 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 759959). 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.*