# NM_004444.5(EPHB4):c.52+14del

https://sugi.bio/variant/ephb4-c-52-plus-14del

## Summary

**EPHB4 c.52+14del** is classified **Benign** in EPHB4 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-04). Common (popmax 37.3%, mid) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs35907339 · 4 submitters · common (popmax 37.3%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the EPHB4 gene that is classified as benign — not considered disease-causing, submitted by 4 submitters.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [EPHB4](https://sugi.bio/atlas/gene/EPHB4/) |
| Coding change (HGVS c.) | c.52+14del |
| MANE Select transcript | [NM_004444](https://www.ncbi.nlm.nih.gov/nuccore/NM_004444) |
| dbSNP | [rs35907339](https://www.ncbi.nlm.nih.gov/snp/rs35907339/) |
| Variant type | Deletion |
| Location | chr7:100826965-100826965 (GRCh38) |
| ClinVar | [VCV811642](https://www.ncbi.nlm.nih.gov/clinvar/variation/811642/) |

**All HGVS expressions:** `NC_000007.13:g.100424587del`, `NC_000007.14:g.100826965del`, `NG_052671.1:g.5557del`, `NM_001363494.1:c.-64del`, `NM_004444.5:c.52+14del`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 37.3%, mid) — too common for a highly-penetrant pathogenic allele.

- **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 -0.456, GERP -2.34, phastCons 0.01 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 6.544**. 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.*
- Splice region: **near-intronic (+14 nt from the splice site)**.
- Non-coding constraint (Gnocchi): **Z -1.23**, o/e 1.09 (1 kb window 100,826,000–100,827,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- 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.
- Population frequency (gnomAD v4.1): grpmax **37.3%** (mid) · FAF95 35.9% · FAF99 35.4% · 2,043/5,482 in the highest group · 373,477/1,423,328 alleles overall — common (popmax 37.3%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 37.3% | 3 |
| Ashkenazi Jewish (not grpmax-eligible) | 33.4% | 3 |
| Finnish (not grpmax-eligible) | 31.1% | 3 |
| European (non-Finnish) | 27.5% | 4 |
| South Asian | 26.1% | 4 |
| Remaining individuals (not grpmax-eligible) | 25.4% | 4 |
| African / African-American | 19.2% | 5 |
| Admixed American | 17% | 6 |
| Amish (not grpmax-eligible) | 17% | 6 |
| East Asian | 0.333% | 300 |

*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}

**EPHB4** population constraint: LOEUF 0.645, pLI 4.3123e-06, missense-Z 1.6946. *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):

- **EPHB4-associated vascular malformation spectrum** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 82.46, 48% of residues very-high.

**23 experimental structure(s)** (PDB): [2BBA](https://www.rcsb.org/structure/2BBA), [2E7H](https://www.rcsb.org/structure/2E7H), [2HLE](https://www.rcsb.org/structure/2HLE), [2QKQ](https://www.rcsb.org/structure/2QKQ), [2VWU](https://www.rcsb.org/structure/2VWU), [2VWV](https://www.rcsb.org/structure/2VWV).

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

*Describes the biological roles of EPHB4 (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:** EPHB4's established molecular role includes ephrin receptor activity.


### Pathways affected {#pathways}

EPHB4 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [EPH-ephrin mediated repulsion of cells](https://reactome.org/content/detail/R-HSA-3928665) | curated |
| [EPH-Ephrin signaling](https://reactome.org/content/detail/R-HSA-2682334) | electronic |
| [EPHB-mediated forward signaling](https://reactome.org/content/detail/R-HSA-3928662) | electronic |
| [Ephrin signaling](https://reactome.org/content/detail/R-HSA-3928664) | electronic |

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

**Molecular function:** ephrin receptor activity.

**Biological process:** angiogenesis, cell migration involved in sprouting angiogenesis, cell adhesion, ephrin receptor signaling pathway.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-04.

**Submitter consensus:** unanimous (4/4 Benign).

**Submission history:** 4 submissions (2020–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2020-08-12 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |

**Reported phenotype names (ClinVar):** not provided, not specified, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related EPHB4 variant pages (same residue, condition, or type): [EPHB4 c.124-11_124-9del](/variant/ephb4-c-124-minus-11-124-minus-9del), [EPHB4 c.52+14_52+15del](/variant/ephb4-c-52-plus-14-52-plus-15del), [EPHB4 c.1691_1691+10del](/variant/ephb4-c-1691-1691-plus-10del), [EPHB4 c.50_52+2del](/variant/ephb4-c-50-52-plus-2del), [EPHB4 p.Ala153fs](/variant/ephb4-p-ala153fs), [EPHB4 p.Ala476fs](/variant/ephb4-p-ala476fs), [EPHB4 p.Ala800fs](/variant/ephb4-p-ala800fs), [EPHB4 p.Arg240fs](/variant/ephb4-p-arg240fs).

### 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 811642). 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.*