# NM_001114753.3(ENG):c.1041G>A (p.Lys347=)

https://sugi.bio/variant/eng-p-lys347

## Summary

**ENG p.Lys347= (c.1041G>A)** is classified **Likely benign** in ENG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-04). Very rare (popmax 0.0022%, sas); Associated with Cardiovascular phenotype.

**At a glance:** Likely benign · review: Single submitter · 1 submitter · 1 linked condition · very rare (popmax 0.0022%, sas)

## For patients & families {#patients}

This is a change in the ENG gene that is classified as likely benign — not considered disease-causing, 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.Lys347= |
| Coding change (HGVS c.) | c.1041G>A |
| MANE Select transcript | [NM_001114753](https://www.ncbi.nlm.nih.gov/nuccore/NM_001114753) |
| Variant type | single nucleotide variant |
| Location | chr9:127824397-127824397 (GRCh38) |
| ClinVar | [VCV3844878](https://www.ncbi.nlm.nih.gov/clinvar/variation/3844878/) |

**All HGVS expressions:** `LRG_589:g.35372G>A`, `LRG_589t1:c.1041G>A`, `LRG_589t2:c.1041G>A`, `NC_000009.11:g.130586676C>T`, `NC_000009.12:g.127824397C>T`, `NG_009551.1:g.35372G>A`, `NM_000118.4:c.1041G>A`, `NM_001114753.3:c.1041G>A`, `NM_001278138.2:c.495G>A`, `NM_001406715.1:c.1041G>A`

## 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 1.03, GERP -0.759 — weakly conserved position
- CADD: **PHRED 10.57**. 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 (C>A, Δ0.37 acceptor 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 **0.0022%** (sas) · FAF95 0.000365% · FAF99 0.000137% · 2/91,082 in the highest group · 2/1,613,850 alleles overall — very rare (popmax 0.0022%, sas).

*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}


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.


### 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-03-04.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-03-04 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **347** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ENG p.Lys347Ter](/variant/eng-p-lys347ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ENG variant pages (same residue, condition, or type): [ENG p.Lys347Asn](/variant/eng-p-lys347asn), [ENG p.Lys347Ter](/variant/eng-p-lys347ter), [ENG p.Lys347Arg](/variant/eng-p-lys347arg), [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), [ENG c.1687-1G>A](/variant/eng-c-1687-minus-1g-a), [ENG c.219+1G>A](/variant/eng-c-219-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 3844878). 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.*