# NM_001114753.3(ENG):c.1586G>A (p.Arg529His)

https://sugi.bio/variant/eng-p-arg529his

## Summary

**ENG p.Arg529His (c.1586G>A)** is classified **Pathogenic** in ENG (ClinVar, Expert panel, 11 submitters; last evaluated 2024-09-11). AlphaMissense: ambiguous (0.3934); Very rare (popmax 0.00133%, afr); Associated with telangiectasia, hereditary hemorrhagic, type 1.

**At a glance:** Pathogenic · review: Expert panel · rsID rs863223538 · 11 submitters · 2 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00133%, afr)

## For patients & families {#patients}

This is a change in the ENG gene that is considered disease-causing, submitted by 11 submitters, 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.Arg529His |
| Coding change (HGVS c.) | c.1586G>A |
| MANE Select transcript | [NM_001114753](https://www.ncbi.nlm.nih.gov/nuccore/NM_001114753) |
| dbSNP | [rs863223538](https://www.ncbi.nlm.nih.gov/snp/rs863223538/) |
| Variant type | single nucleotide variant |
| Location | chr9:127818220-127818220 (GRCh38) |
| ClinVar | [VCV213212](https://www.ncbi.nlm.nih.gov/clinvar/variation/213212/) |

**All HGVS expressions:** `LRG_589:g.41549G>A`, `LRG_589t1:c.1586G>A`, `LRG_589t2:c.1586G>A`, `NC_000009.11:g.130580499C>T`, `NC_000009.12:g.127818220C>T`, `NG_009551.1:g.41549G>A`, `NM_000118.4:c.1586G>A`, `NM_001114753.3:c.1586G>A`, `NM_001278138.2:c.1040G>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense and REVEL make no call here — the available evidence is described below.

- AlphaMissense **ambiguous** (0.3934) — no call either way
- REVEL 0.579 (indeterminate)
- SaProt LLR -12.202 (damaging)
- Conservation: phyloP 4.607, GERP 1.6, phastCons 1 — highly conserved
- CADD: **PHRED 27.1**. 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 (gnomAD v4.1): grpmax **0.00133%** (afr) · 1/75,038 in the highest group · 3/1,461,874 alleles overall — very rare (popmax 0.00133%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.00133% | 75,038 |
| South Asian | 0.0011% | 91,084 |
| European (non-Finnish) | 8.47e-05% | 1,180,025 |

*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 **529** lies in a β-strand; a disulfide bond; the zp domain; a UniProt-annotated variant site (in hht1).

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.Arg529His 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 Expert panel *(reviewed by expert panel)*, last evaluated 2024-09-11.

**Submitter consensus:** conflicting (6 Likely pathogenic, 4 Pathogenic, 1 pathogenic).

**Submission history:** 11 submissions (2017–2026); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — Hereditary Hemorrhagic Telangiectasia VCEP (telangiectasia, hereditary hemorrhagic, type 1). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PP4_Moderate`, `PP1_Strong`, `PM2_Supporting`, `PS4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_001114753.3: c.1586G>A variant in ENG is a missense variant predicted to cause substitution of arginine by histidine at amino acid 529 (p.Arg529His). This variant has been reported in more than 10 probands with a phenotype consistent with HHT (PS4; PMID: 22991266, 16752392, Internal lab contributors). At least one patient's phenotype meets Curacao Criteria for HHT, and sequencing and large deletion/duplication analysis was performed for ENG and ACVRL1, which is highly specific for HHT (PP4_Moderate; Internal lab contributors). The variant has been reported to segregate with HHT in more than 20 affected family members from multiple families (PP1_Strong; Internal lab contributors). The overall minor allele frequency in gnomAD v2.1.1 is 0.000004 (1/251282 alleles), which is lower than the ClinGen Hereditary Hemorrhagic Telangiectasia VCEP threshold (<6 total alleles) for PM2_Supporting, meeting this criterion (PM2_Supporting). The computational predictor REVEL gives a score of 0.579, which is neither above nor below the thresholds predicting a damaging or benign impact on ENG function. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary hemorrhagic telangiectasia based on the ACMG/AMP criteria applied, as specified by the ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel: PM2_Supporting, PS4, PP4_Moderate, PP1_Strong (specifications version 1.1.0; 09/11/2024).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50037 · approved 2024-09-11 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/59ed568c-8b34-41b1-baa2-f56a0adfb060).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-12-09 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-11-25 |
| ClinGen Hereditary Hemorrhagic Telangiectasia Variant Curation Expert Panel, ClinGen | Pathogenic | reviewed by expert panel | curation | 2024-09-11 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | no assertion criteria provided | clinical testing | 2024-01-31 |
| Center of Genomic medicine, Geneva, University Hospital of Geneva | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-05-16 |
| Clinical Genomics Laboratory, Washington University in St. Louis | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-03-26 |
| Institute of Human Genetics, University of Leipzig Medical Center | pathogenic | criteria provided, single submitter | clinical testing | 2025-10-22 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2025-03-04 |
| GeneDx | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-08-05 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-11-21 |

## Associated conditions {#conditions}

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

## Same-residue context {#hotspot}

Residue **529** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ENG p.Arg529fs](/variant/eng-p-arg529fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ENG variant pages (same residue, condition, or type): [ENG p.Arg529Cys](/variant/eng-p-arg529cys), [ENG p.Arg529fs](/variant/eng-p-arg529fs), [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), [ENG p.Gly603Arg](/variant/eng-p-gly603arg), [ENG p.Leu221Pro](/variant/eng-p-leu221pro).

### 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 213212). 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.*