# NM_001114753.3(ENG):c.1509_1510insCCAC (p.Val504fs)

https://sugi.bio/variant/eng-p-val504fs

## Summary

**ENG p.Val504fs (c.1509_1510insCCAC)** is classified **Pathogenic** in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-27). No gnomAD frequency available for this variant; Associated with Cardiovascular phenotype.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2539059682 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ENG gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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.Val504fs |
| Coding change (HGVS c.) | c.1509_1510insCCAC |
| MANE Select transcript | [NM_001114753](https://www.ncbi.nlm.nih.gov/nuccore/NM_001114753) |
| dbSNP | [rs2539059682](https://www.ncbi.nlm.nih.gov/snp/rs2539059682/) |
| Variant type | Insertion |
| Location | chr9:127818296-127818297 (GRCh38) |
| ClinVar | [VCV1774126](https://www.ncbi.nlm.nih.gov/clinvar/variation/1774126/) |

**All HGVS expressions:** `LRG_589:g.41472_41473insCCAC`, `LRG_589t1:c.1509_1510insCCAC`, `LRG_589t2:c.1508_1509insCCCA`, `NC_000009.11:g.130580576_130580577insTGGG`, `NC_000009.12:g.127818297_127818298insTGGG`, `NG_009551.1:g.41472_41473insCCAC`, `NM_000118.4:c.1508_1509insCCCA`, `NM_001114753.3:c.1509_1510insCCAC`, `NM_001278138.2:c.963_964insCCAC`

## 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 0.232, GERP -0.593, phastCons 0.001 — 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 12 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 insertion 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, 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 **504** lies in a β-strand; a disulfide bond; the zp domain; a UniProt-annotated variant site (in hht1; likely benign).

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.Val504fs falls in the zp domain.


### 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-27.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2021-07-27 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Cardiovascular phenotype.

## Similar variants {#similar}

Related ENG variant pages (same residue, condition, or type): [ENG p.Val504Met](/variant/eng-p-val504met), [ENG p.Glu195fs](/variant/eng-p-glu195fs), [ENG p.Leu147fs](/variant/eng-p-leu147fs), [ENG p.Val504Glu](/variant/eng-p-val504glu), [ENG p.Val504=](/variant/eng-p-val504), [ENG c.1134+1G>T](/variant/eng-c-1134-plus-1g-t), [ENG c.1311+2T>A](/variant/eng-c-1311-plus-2t-a), [ENG c.1428+1G>A](/variant/eng-c-1428-plus-1g-a).

### 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 1774126). 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.*