# NM_017617.5(NOTCH1):c.4988G>T (p.Arg1663Leu)

https://sugi.bio/variant/notch1-p-arg1663leu

## Summary

**NOTCH1 p.Arg1663Leu (c.4988G>T)** is classified **Uncertain significance** in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-10). AlphaMissense: likely benign (0.2308); Very rare (popmax 0.000263%, nfe); Associated with Adams-Oliver syndrome 5.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs749490844 · 1 submitter · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.000263%, nfe)

## For patients & families {#patients}

This is a change in the NOTCH1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to Adams-Oliver syndrome 5.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0016049/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.Arg1663Leu |
| Coding change (HGVS c.) | c.4988G>T |
| MANE Select transcript | [NM_017617](https://www.ncbi.nlm.nih.gov/nuccore/NM_017617) |
| dbSNP | [rs749490844](https://www.ncbi.nlm.nih.gov/snp/rs749490844/) |
| Variant type | single nucleotide variant |
| Location | chr9:136504703-136504703 (GRCh38) |
| ClinVar | [VCV2012405](https://www.ncbi.nlm.nih.gov/clinvar/variation/2012405/) |

**All HGVS expressions:** `LRG_1122:g.46084G>T`, `LRG_1122t1:c.4988G>T`, `NC_000009.11:g.139399155C>A`, `NC_000009.12:g.136504703C>A`, `NG_007458.1:g.46084G>T`, `NM_017617.5:c.4988G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2308)
- REVEL 0.301 (indeterminate)
- SaProt LLR -10.32 (damaging) — differs from AlphaMissense
- → **In-silico consensus:** SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate
- Conservation: phyloP 7.314, GERP 1.72, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 23.8**. 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: **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 **0.000263%** (nfe) · FAF95 7e-05% · FAF99 1.9e-05% · 3/1,139,106 in the highest group · 3/1,534,692 alleles overall — very rare (popmax 0.000263%, nfe).

*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 3/3, triplosensitivity 0/3. *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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-06-10.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-10 |

## Associated conditions {#conditions}

[Adams-Oliver syndrome 5](https://sugi.bio/atlas/disease/adams-oliver-syndrome-5/).

**Reported phenotype names (ClinVar):** Adams-Oliver syndrome 5.

## Similar variants {#similar}

Related NOTCH1 variant pages (same residue, condition, or type): [NOTCH1 p.Arg1663Gln](/variant/notch1-p-arg1663gln), [NOTCH1 p.Arg1663Trp](/variant/notch1-p-arg1663trp), [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 2026-10-14); 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 2026-10-14); 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 2012405). 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.*