# NM_017617.5(NOTCH1):c.4987C>T (p.Arg1663Trp)

https://sugi.bio/variant/notch1-p-arg1663trp

## Summary

**NOTCH1 p.Arg1663Trp (c.4987C>T)** is classified **Conflicting classifications of pathogenicity** in NOTCH1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-25). AlphaMissense: likely benign (0.1647); Very rare (popmax 0.00246%, eas); Associated with familial thoracic aortic aneurysm and aortic dissection.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs769050541 · 4 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00246%, eas)

## For patients & families {#patients}

This is a change in the NOTCH1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to familial thoracic aortic aneurysm and aortic dissection.

*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) | Adolescent, Adult, Childhood |
| Clinical trials | 2 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NOTCH1 is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Familial thoracic aortic aneurysm and aortic dissection** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Cutis marmorata — Very frequent (99-80%)
- Abnormality of connective tissue — Very frequent (99-80%)
- Cystic medial necrosis of the aorta — Very frequent (99-80%)
- Abnormality iris morphology — Frequent (79-30%)
- Hypertension — Frequent (79-30%)
- Cardiomegaly — Frequent (79-30%)
- Aortic regurgitation — Frequent (79-30%)
- Coronaryartery atherosclerosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002249/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NOTCH1](https://sugi.bio/atlas/gene/NOTCH1/) |
| Protein change (HGVS p.) | p.Arg1663Trp |
| Coding change (HGVS c.) | c.4987C>T |
| MANE Select transcript | [NM_017617](https://www.ncbi.nlm.nih.gov/nuccore/NM_017617) |
| dbSNP | [rs769050541](https://www.ncbi.nlm.nih.gov/snp/rs769050541/) |
| Variant type | single nucleotide variant |
| Location | chr9:136504704-136504704 (GRCh38) |
| ClinVar | [VCV1744553](https://www.ncbi.nlm.nih.gov/clinvar/variation/1744553/) |

**All HGVS expressions:** `LRG_1122:g.46083C>T`, `LRG_1122t1:c.4987C>T`, `NC_000009.11:g.139399156G>A`, `NC_000009.12:g.136504704G>A`, `NG_007458.1:g.46083C>T`, `NM_017617.5:c.4987C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1647)
- REVEL 0.497 (indeterminate)
- SaProt LLR -11.753 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL makes no call
- SpliceAI predicts **donor gain** (Δ 0.29) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 9.381, GERP 1.72, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 33.0**. 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 (136,503,317–136,515,546), spanning 12,229 bp. Chi-square p 5.9e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.29**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.29**.
- Pangolin: Δ**0.22** (gain), gain 0.22 / loss 0.13. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00246%** (eas) · FAF95 0.00115% · FAF99 0.000932% · 1/40,718 in the highest group · 23/1,535,020 alleles overall — very rare (popmax 0.00246%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00246% | 40,718 |
| European (non-Finnish) | 0.00176% | 56,965 |
| African / African-American | 0.00138% | 72,648 |
| South Asian | 0.00121% | 82,436 |

*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}

**NOTCH1** population constraint: LOEUF 0.217, pLI 1, missense-Z 3.6962; 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):

- **NOTCH1-related AOS spectrum disorder** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 59.74, 3% of residues very-high.

**29 experimental structure(s)** (PDB): [1PB5](https://www.rcsb.org/structure/1PB5), [1TOZ](https://www.rcsb.org/structure/1TOZ), [1YYH](https://www.rcsb.org/structure/1YYH), [2F8X](https://www.rcsb.org/structure/2F8X), [2F8Y](https://www.rcsb.org/structure/2F8Y), [2HE0](https://www.rcsb.org/structure/2HE0) — incl. mutant structure 2HE0.

## What this gene does {#gene-function}

*Describes the biological roles of NOTCH1 (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:** NOTCH1's established molecular role includes transcription coactivator activity. In Reactome, NOTCH1 is annotated in disease pathway(s) including **Constitutive Signaling by NOTCH1 HD Domain Mutants**, **Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants**.

**Disease mechanism (Reactome):** NOTCH1 loss or alteration is curated in [Constitutive Signaling by NOTCH1 HD Domain Mutants](https://reactome.org/content/detail/R-HSA-2691232), [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862), [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606).

### Pathways affected {#pathways}

NOTCH1 participates in **22 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by NOTCH1 HD Domain Mutants](https://reactome.org/content/detail/R-HSA-2691232) | other |
| ⚕ [Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2894862) | other |
| ⚕ [Constitutive Signaling by NOTCH1 PEST Domain Mutants](https://reactome.org/content/detail/R-HSA-2644606) | other |
| ⚕ [Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant](https://reactome.org/content/detail/R-HSA-2660826) | other |
| ⚕ [Defective LFNG causes SCDO3](https://reactome.org/content/detail/R-HSA-5083630) | other |
| ⚕ [Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling](https://reactome.org/content/detail/R-HSA-2644607) | other |
| [Transcriptional regulation of multiciliogenesis](https://reactome.org/content/detail/R-HSA-9945556) | curated |
| [Activated NOTCH1 Transmits Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-2122948) | other |
| [Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)](https://reactome.org/content/detail/R-HSA-9976102) | electronic |
| [Formation of paraxial mesoderm](https://reactome.org/content/detail/R-HSA-9793380) | other |
| [NFE2L2 regulating tumorigenic genes](https://reactome.org/content/detail/R-HSA-9818030) | other |
| [NOTCH1 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-2122947) | other |
| [NOTCH3 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013508) | other |
| [NOTCH4 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013695) | other |
| [Notch-HLH transcription pathway](https://reactome.org/content/detail/R-HSA-350054) | other |
| [Pre-NOTCH Processing in Golgi](https://reactome.org/content/detail/R-HSA-1912420) | other |
| [Pre-NOTCH Processing in the Endoplasmic Reticulum](https://reactome.org/content/detail/R-HSA-1912399) | other |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | other |
| [RUNX3 regulates NOTCH signaling](https://reactome.org/content/detail/R-HSA-8941856) | other |
| [Regulation of NFE2L2 gene expression](https://reactome.org/content/detail/R-HSA-9818749) | other |
| [Regulation of gene expression in late stage (branching morphogenesis) pancreatic bud precursor cells](https://reactome.org/content/detail/R-HSA-210744) | other |
| [Somitogenesis](https://reactome.org/content/detail/R-HSA-9824272) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription coactivator activity, transmembrane signaling receptor activity, identical protein binding.

**Biological process:** negative regulation of transcription by RNA polymerase II, epithelial to mesenchymal transition, outflow tract morphogenesis, aortic valve morphogenesis, pulmonary valve morphogenesis, mitral valve formation.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-06-25.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-13 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-25 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-06 |

## Associated conditions {#conditions}

[familial thoracic aortic aneurysm and aortic dissection](https://sugi.bio/atlas/disease/familial-thoracic-aortic-aneurysm-and-aortic-dissection/), [Adams-Oliver syndrome 5](https://sugi.bio/atlas/disease/adams-oliver-syndrome-5/).

**Reported phenotype names (ClinVar):** Familial thoracic aortic aneurysm and aortic dissection, Adams-Oliver syndrome 5, not provided, not specified, Thoracic aortic aneurysms and dissections, none provided, AllHighlyPenetrant.

## Similar variants {#similar}

Related NOTCH1 variant pages (same residue, condition, or type): [NOTCH1 p.Arg1663Gln](/variant/notch1-p-arg1663gln), [NOTCH1 p.Arg1663Leu](/variant/notch1-p-arg1663leu), [NOTCH1 c.1099+1G>T](/variant/notch1-c-1099-plus-1g-t), [NOTCH1 c.3511-1G>A](/variant/notch1-c-3511-minus-1g-a), [NOTCH1 p.Arg1107Ter](/variant/notch1-p-arg1107ter), [NOTCH1 p.Arg448Ter](/variant/notch1-p-arg448ter), [NOTCH1 p.Arg56Ter](/variant/notch1-p-arg56ter), [NOTCH1 p.Asp1517Asn](/variant/notch1-p-asp1517asn).

### 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 2026-07-14); 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 1744553). 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.*