# NM_001955.5(EDN1):c.130C>T (p.Pro44Ser)

https://sugi.bio/variant/edn1-p-pro44ser

## Summary

**EDN1 p.Pro44Ser (c.130C>T)** is classified **Uncertain significance** in EDN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely benign (0.0715); Very rare (popmax 0.00659%, sas); Associated with Inborn genetic diseases.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.00659%, sas)

## For patients & families {#patients}

This is a change in the EDN1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Inborn genetic diseases.

*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 | [EDN1](https://sugi.bio/atlas/gene/EDN1/) |
| Protein change (HGVS p.) | p.Pro44Ser |
| Coding change (HGVS c.) | c.130C>T |
| MANE Select transcript | [NM_001955](https://www.ncbi.nlm.nih.gov/nuccore/NM_001955) |
| Variant type | single nucleotide variant |
| Location | chr6:12292406-12292406 (GRCh38) |
| ClinVar | [VCV4246624](https://www.ncbi.nlm.nih.gov/clinvar/variation/4246624/) |

**All HGVS expressions:** `NC_000006.11:g.12292639C>T`, `NC_000006.12:g.12292406C>T`, `NG_016196.1:g.7111C>T`, `NG_016196.2:g.40924C>T`, `NM_001168319.2:c.127C>T`, `NM_001416563.1:c.130C>T`, `NM_001416564.1:c.130C>T`, `NM_001416565.1:c.130C>T`, `NM_001955.5:c.130C>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0715)
- REVEL 0.179 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.9 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.066, GERP 0.829 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.028**. 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.*
- Regional missense constraint: **o/e 0.93** across the covering region of the MANE Select transcript (12,290,630–12,296,064), spanning 5,434 bp. Chi-square p 0.26. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for EDN1 (152 scored positions, the nearest 30 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00659%** (sas) · FAF95 0.00286% · FAF99 0.00195% · 6/91,090 in the highest group · 24/1,614,042 alleles overall — very rare (popmax 0.00659%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00659% | 15,182 |
| Remaining individuals (not grpmax-eligible) | 0.0032% | 31,244 |
| European (non-Finnish) | 0.00136% | 73,753 |

*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}

**EDN1** population constraint: LOEUF 0.84, pLI 0.0045322, missense-Z 0.71523. *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):

- **auriculocondylar syndrome** — Limited (AR)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 65.62, 1% of residues very-high.

**17 experimental structure(s)** (PDB): [1EDN](https://www.rcsb.org/structure/1EDN), [1EDP](https://www.rcsb.org/structure/1EDP), [1T7H](https://www.rcsb.org/structure/1T7H), [1V6R](https://www.rcsb.org/structure/1V6R), [5GLH](https://www.rcsb.org/structure/5GLH), [6DK5](https://www.rcsb.org/structure/6DK5).

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

*Describes the biological roles of EDN1 (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:** EDN1's established molecular role includes cytokine activity.


### Pathways affected {#pathways}

EDN1 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [G alpha (q) signalling events](https://reactome.org/content/detail/R-HSA-416476) | curated |
| [Peptide ligand-binding receptors](https://reactome.org/content/detail/R-HSA-375276) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |

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

**Molecular function:** cytokine activity, hormone activity, endothelin A receptor binding, endothelin B receptor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, regulation of systemic arterial blood pressure by endothelin, intracellular calcium ion homeostasis, cell surface receptor signaling pathway, G protein-coupled receptor signaling pathway, cell-cell signaling.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-06-24.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-24 |

## Associated conditions {#conditions}

[Inborn genetic diseases](https://sugi.bio/atlas/disease/inborn-genetic-diseases/).

**Reported phenotype names (ClinVar):** Inborn genetic diseases.

## Similar variants {#similar}

Related EDN1 variant pages (same residue, condition, or type): [EDN1 p.Cys155Tyr](/variant/edn1-p-cys155tyr), [EDN1 p.Ala26Thr](/variant/edn1-p-ala26thr), [EDN1 p.Ala30Glu](/variant/edn1-p-ala30glu), [EDN1 p.Arg108Gly](/variant/edn1-p-arg108gly), [EDN1 p.Arg175Thr](/variant/edn1-p-arg175thr), [EDN1 p.Arg178Ser](/variant/edn1-p-arg178ser), [EDN1 p.Arg203Cys](/variant/edn1-p-arg203cys), [EDN1 p.Arg203His](/variant/edn1-p-arg203his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 4246624). 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.*