# NM_004444.5(EPHB4):c.591C>T (p.Cys197=)

https://sugi.bio/variant/ephb4-p-cys197

## Summary

**EPHB4 p.Cys197= (c.591C>T)** is classified **Likely benign** in EPHB4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-14). Ultra-rare (popmax 0.0165%, mid); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1180723589 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0165%, mid)

## For patients & families {#patients}

This is a change in the EPHB4 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to Cardiovascular phenotype.

*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/) |
| Protein change (HGVS p.) | p.Cys197= |
| Coding change (HGVS c.) | c.591C>T |
| MANE Select transcript | [NM_004444](https://www.ncbi.nlm.nih.gov/nuccore/NM_004444) |
| dbSNP | [rs1180723589](https://www.ncbi.nlm.nih.gov/snp/rs1180723589/) |
| Variant type | single nucleotide variant |
| Location | chr7:100822488-100822488 (GRCh38) |
| ClinVar | [VCV1750489](https://www.ncbi.nlm.nih.gov/clinvar/variation/1750489/) |

**All HGVS expressions:** `NC_000007.13:g.100420110G>A`, `NC_000007.14:g.100822488G>A`, `NG_052671.1:g.10034C>T`, `NM_004444.5:c.591C>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 -0.497, GERP -4.75 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.497**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.43 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0165%** (mid) · FAF95 0.00259% · FAF99 0.00233% · 1/6,060 in the highest group · 45/1,613,000 alleles overall — ultra-rare (popmax 0.0165%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0165% | 6,060 |
| European (non-Finnish) | 0.00348% | 28,770 |
| African / African-American | 0.00266% | 37,532 |
| South Asian | 0.0011% | 91,018 |

*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}

Residue **197** lies in a UniProt-annotated variant site (in cmavm2); the eph lbd domain.

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. p.Cys197= falls in the eph lbd domain.


### 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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-10-14.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2020–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-12-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-10-14 |

## Associated conditions {#conditions}

[Cardiovascular phenotype](https://sugi.bio/atlas/disease/cardiovascular-phenotype/).

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

## Same-residue context {#hotspot}

Residue **197** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [EPHB4 p.Cys197Gly](/variant/ephb4-p-cys197gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related EPHB4 variant pages (same residue, condition, or type): [EPHB4 p.Cys197Arg](/variant/ephb4-p-cys197arg), [EPHB4 p.Cys197Phe](/variant/ephb4-p-cys197phe), [EPHB4 p.Cys197Gly](/variant/ephb4-p-cys197gly), [EPHB4 p.Cys197Tyr](/variant/ephb4-p-cys197tyr), [EPHB4 c.1870+5G>C](/variant/ephb4-c-1870-plus-5g-c), [EPHB4 p.Ala262Val](/variant/ephb4-p-ala262val), [EPHB4 p.Ala345Gly](/variant/ephb4-p-ala345gly), [EPHB4 p.Ala931Thr](/variant/ephb4-p-ala931thr).

### 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 1750489). 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.*