# NM_001114753.3(ENG):c.721_725del (p.Ser241fs)

https://sugi.bio/variant/eng-p-ser241fs

## Summary

**ENG p.Ser241fs (c.721_725del)** is classified **Pathogenic** in ENG (ClinVar, Multiple submitters, 7 submitters; last evaluated 2024-12-20). No gnomAD frequency available for this variant; Associated with Cardiovascular phenotype.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1064794219 · 7 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ENG gene that is considered disease-causing, submitted by 7 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 | [ENG](https://sugi.bio/atlas/gene/ENG/) |
| Protein change (HGVS p.) | p.Ser241fs |
| Coding change (HGVS c.) | c.721_725del |
| MANE Select transcript | [NM_001114753](https://www.ncbi.nlm.nih.gov/nuccore/NM_001114753) |
| dbSNP | [rs1064794219](https://www.ncbi.nlm.nih.gov/snp/rs1064794219/) |
| Variant type | Deletion |
| Location | chr9:127825322-127825326 (GRCh38) |
| ClinVar | [VCV419981](https://www.ncbi.nlm.nih.gov/clinvar/variation/419981/) |

**All HGVS expressions:** `LRG_589:g.34443_34447del`, `LRG_589t1:c.721_725del`, `LRG_589t2:c.718_722del`, `NC_000009.11:g.130587604_130587608del`, `NC_000009.12:g.127825325_127825329del`, `NG_009551.1:g.34443_34447del`, `NM_000118.2:c.721_725del`, `NM_000118.3:c.721_725delAGCTG`, `NM_000118.4:c.718_722delCTGAG`, `NM_001114753.2:c.721_725del`, `NM_001114753.3:c.721_725del`, `NM_001278138.2:c.175_179del`, `NM_001406715.1:c.718_722delCTGAG`

## 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 1.35, GERP -0.68, phastCons 0.612 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.374, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 15**, so the transcript is predicted to undergo NMD.
- 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: **no gnomAD frequency available for this variant** — 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 3/3, triplosensitivity 0/3. *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 **241** 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.Ser241fs 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-20.

**Submitter consensus:** unanimous (7/7 Pathogenic).

**Submission history:** 7 submissions (2019–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2019-07-23 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-03-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-17 |
| Fulgent Genetics, Fulgent Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-05-30 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-05-22 |
| Mayo Clinic Laboratories, Mayo Clinic | Pathogenic | criteria provided, single submitter | clinical testing | 2023-09-28 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-12-20 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype, not provided, Hereditary hemorrhagic telangiectasia, Telangiectasia, hereditary hemorrhagic, type 1, ENG-related disorder, ENG-related condition, ENG-related disorders, none provided, Osler Weber Rendu syndrome type 1, ENG-Related Hereditary Hemorrhagic Telangiectasia.

## Similar variants {#similar}

Related ENG variant pages (same residue, condition, or type): [ENG p.Ser241Asn](/variant/eng-p-ser241asn), [ENG p.Ser241=](/variant/eng-p-ser241), [ENG p.Val568fs](/variant/eng-p-val568fs), [ENG c.1687delG](/variant/eng-c-1687delg), [ENG p.Ala312fs](/variant/eng-p-ala312fs), [ENG p.Ala55fs](/variant/eng-p-ala55fs), [ENG p.Arg232_Thr233del](/variant/eng-p-arg232-thr233del), [ENG p.Arg399fs](/variant/eng-p-arg399fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 419981). 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.*