# NM_001114753.3(ENG):c.673C>T (p.Pro225Ser)

https://sugi.bio/variant/eng-p-pro225ser

## Summary

**ENG p.Pro225Ser (c.673C>T)** is classified **Uncertain significance** in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-30). AlphaMissense: likely benign (0.1537); No allele count reported in gnomAD v4.1 (AN 1,587,894); Associated with telangiectasia, hereditary hemorrhagic, type 1.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1554810373 · 1 submitter · 1 linked condition · AlphaMissense likely benign · no allele count reported in gnomAD v4.1 (AN 1,587,894)

## For patients & families {#patients}

This is a change in the ENG gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to telangiectasia, hereditary hemorrhagic, type 1.

*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) | Autosomal dominant |
| Age of onset (of this condition) | All ages |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ENG is a diagnostic-grade gene on 7 Genomics England panels |

**Commonly reported features of Hereditary hemorrhagic telangiectasia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Lip telangiectasia — Very frequent (99-80%)
- Tongue telangiectasia — Very frequent (99-80%)
- Epistaxis — Very frequent (99-80%)
- Nasal mucosa telangiectasia — Very frequent (99-80%)
- Telangiectasia — Very frequent (99-80%)
- Spontaneous, recurrent epistaxis — Very frequent (99-80%)
- Mucosal telangiectasiae — Very frequent (99-80%)
- Telangiectasia of the skin — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0024627/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ENG](https://sugi.bio/atlas/gene/ENG/) |
| Protein change (HGVS p.) | p.Pro225Ser |
| Coding change (HGVS c.) | c.673C>T |
| MANE Select transcript | [NM_001114753](https://www.ncbi.nlm.nih.gov/nuccore/NM_001114753) |
| dbSNP | [rs1554810373](https://www.ncbi.nlm.nih.gov/snp/rs1554810373/) |
| Variant type | single nucleotide variant |
| Location | chr9:127825711-127825711 (GRCh38) |
| ClinVar | [VCV1321216](https://www.ncbi.nlm.nih.gov/clinvar/variation/1321216/) |

**All HGVS expressions:** `LRG_589:g.34058C>T`, `LRG_589t1:c.673C>T`, `LRG_589t2:c.673C>T`, `NC_000009.11:g.130587990G>A`, `NC_000009.12:g.127825711G>A`, `NG_009551.1:g.34058C>T`, `NM_000118.4:c.673C>T`, `NM_001114753.3:c.673C>T`, `NM_001278138.2:c.127C>T`, `NM_001406715.1:c.673C>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** (0.1537)
- REVEL 0.019 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.108 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.347, GERP 1.85, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 18.72**. 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 0.86** across the covering region of the MANE Select transcript (127,815,685–127,854,355), spanning 38,670 bp. Chi-square p 5.2e-05. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **no allele count reported in gnomAD v4.1 (AN 1,587,894)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**ENG** population constraint: LOEUF 0.374, pLI 1, missense-Z 1.285; 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):

- **juvenile polyposis syndrome** — Limited (AD)
- **telangiectasia, hereditary hemorrhagic, type 1** — Definitive (AD)

## Protein context {#protein}

Residue **225** lies in the 'required for interaction with gdf2' region; the 'or1, c-terminal part' region.

AlphaFold model confidence (whole protein): pLDDT 80.84, 40% of residues very-high.

**3 experimental structure(s)** (PDB): [5HZV](https://www.rcsb.org/structure/5HZV), [5HZW](https://www.rcsb.org/structure/5HZW), [5I04](https://www.rcsb.org/structure/5I04).

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

*Describes the biological roles of ENG (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:** ENG's established molecular role includes type II transforming growth factor beta receptor binding. p.Pro225Ser falls in the required for interaction with gdf2 region.


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

**Molecular function:** type II transforming growth factor beta receptor binding, galactose binding, glycosaminoglycan binding, coreceptor activity, signaling receptor activator activity, type I transforming growth factor beta receptor binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, vasculogenesis, response to hypoxia, negative regulation of endothelial cell proliferation, positive regulation of systemic arterial blood pressure, regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-03-30.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Molecular Genetics, Royal Melbourne Hospital | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-30 |

## Associated conditions {#conditions}

[telangiectasia, hereditary hemorrhagic, type 1](https://sugi.bio/atlas/disease/telangiectasia-hereditary-hemorrhagic-type-1/).

**Reported phenotype names (ClinVar):** Telangiectasia, hereditary hemorrhagic, type 1, Osler Weber Rendu syndrome type 1, ENG-Related Hereditary Hemorrhagic Telangiectasia.

## Same-residue context {#hotspot}

Residue **225** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ENG p.Pro225fs](/variant/eng-p-pro225fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ENG variant pages (same residue, condition, or type): [ENG p.Pro225Leu](/variant/eng-p-pro225leu), [ENG p.Pro225Thr](/variant/eng-p-pro225thr), [ENG p.Pro225=](/variant/eng-p-pro225), [ENG p.Pro225Ala](/variant/eng-p-pro225ala), [ENG p.Pro225Gln](/variant/eng-p-pro225gln), [ENG p.Pro225Arg](/variant/eng-p-pro225arg), [ENG p.Arg529His](/variant/eng-p-arg529his), [ENG p.Asn423Ser](/variant/eng-p-asn423ser).

### 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 1321216). 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.*