# NM_001114753.3(ENG):c.120C>T (p.Gly40=)

https://sugi.bio/variant/eng-p-gly40

## Summary

**ENG p.Gly40= (c.120C>T)** is classified **Benign/Likely benign** in ENG (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-05-01). Rare (popmax 0.629%, nfe); Associated with Cardiovascular phenotype.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs41522944 · 16 submitters · 3 linked conditions · rare (popmax 0.629%, nfe)

## For patients & families {#patients}

This is a change in the ENG gene that is classified as benign/likely benign — not considered disease-causing, submitted by 16 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.Gly40= |
| Coding change (HGVS c.) | c.120C>T |
| MANE Select transcript | [NM_001114753](https://www.ncbi.nlm.nih.gov/nuccore/NM_001114753) |
| dbSNP | [rs41522944](https://www.ncbi.nlm.nih.gov/snp/rs41522944/) |
| Variant type | single nucleotide variant |
| Location | chr9:127843193-127843193 (GRCh38) |
| ClinVar | [VCV237016](https://www.ncbi.nlm.nih.gov/clinvar/variation/237016/) |

**All HGVS expressions:** `LRG_589:g.16576C>T`, `LRG_589t1:c.120C>T`, `LRG_589t2:c.120C>T`, `NC_000009.11:g.130605472G>A`, `NC_000009.12:g.127843193G>A`, `NG_009551.1:g.16576C>T`, `NM_000118.4:c.120C>T`, `NM_001114753.3:c.120C>T`, `NM_001278138.2:c.-427C>T`, `NM_001406715.1:c.120C>T`

## 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 -0.758, GERP -3.07 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.341**. 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: **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 (gnomAD v4.1): grpmax **0.629%** (nfe) · FAF95 0.617% · FAF99 0.612% · 7,423/1,180,034 in the highest group · 8,164/1,614,206 alleles overall — rare (popmax 0.629%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.629% | 159 |
| Remaining individuals (not grpmax-eligible) | 0.443% | 226 |
| Admixed American | 0.415% | 241 |
| African / African-American | 0.107% | 938 |
| South Asian | 0.0988% | 1,012 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0946% | 1,057 |
| Middle Eastern | 0.0495% | 2,021 |
| Finnish (not grpmax-eligible) | 0.0203% | 4,925 |
| East Asian | 0.00223% | 44,888 |

*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 **40** lies in a disulfide bond; the 'required for interaction with gdf2' region; the 'or1, n-terminal part' region; a β-strand.

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.Gly40= 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-05-01.

**Submitter consensus:** conflicting (8 Benign, 7 Likely benign).

**Submission history:** 21 submissions (2013–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2014-06-30 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2023-01-12 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-05-01 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-12-02 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Likely benign | no assertion criteria provided | clinical testing |  |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2013-02-21 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics, Academic Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| Dr. Peter K. Rogan Lab, Western University |  | no classification provided | in vitro |  |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-04-16 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-23 |

## 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, Telangiectasia, hereditary hemorrhagic, type 1, not specified, Hereditary hemorrhagic telangiectasia, not provided, Cholangiocarcinoma, Melanoma, Acute myeloid leukemia, Uterine corpus endometrial carcinoma, Clear cell carcinoma of kidney.

## Same-residue context {#hotspot}

Residue **40** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ENG p.Gly40fs](/variant/eng-p-gly40fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ENG variant pages (same residue, condition, or type): [ENG p.Gly40Cys](/variant/eng-p-gly40cys), [ENG p.Gly40fs](/variant/eng-p-gly40fs), [ENG p.Gly40_Thr45delinsAla](/variant/eng-p-gly40-thr45delinsala), [ENG p.Arg529His](/variant/eng-p-arg529his), [ENG p.Asn423Ser](/variant/eng-p-asn423ser), [ENG p.Cys382Tyr](/variant/eng-p-cys382tyr), [ENG p.Cys549Gly](/variant/eng-p-cys549gly), [ENG p.Gly331Ser](/variant/eng-p-gly331ser).

### 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 237016). 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.*