# NM_000435.3(NOTCH3):c.6603C>T (p.Pro2201=)

https://sugi.bio/variant/notch3-p-pro2201

## Summary

**NOTCH3 p.Pro2201= (c.6603C>T)** is classified **Conflicting classifications of pathogenicity** in NOTCH3 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-01). Very rare (popmax 0.00844%, sas); Associated with cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs200415679 · 3 submitters · 1 linked condition · very rare (popmax 0.00844%, sas)

## For patients & families {#patients}

This is a change in the NOTCH3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 3 submitters, and is linked to cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, 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) | Adult |
| Prevalence | 1-9 / 100 000 (Europe) |
| Clinical trials | 30 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | NOTCH3 is a diagnostic-grade gene on 15 Genomics England panels |

**Commonly reported features of Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Leukoencephalopathy — Very frequent (99-80%)
- Abnormal cerebral white matter morphology — Very frequent (99-80%)
- Lacunar stroke — Very frequent (99-80%)
- Multifocal hyperintensity of cerebral white matter on MRI — Very frequent (99-80%)
- Emotional lability — Frequent (79-30%)
- Apathy — Frequent (79-30%)
- Stroke — Frequent (79-30%)
- Migraine — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0001049/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [NOTCH3](https://sugi.bio/atlas/gene/NOTCH3/) |
| Protein change (HGVS p.) | p.Pro2201= |
| Coding change (HGVS c.) | c.6603C>T |
| MANE Select transcript | [NM_000435](https://www.ncbi.nlm.nih.gov/nuccore/NM_000435) |
| dbSNP | [rs200415679](https://www.ncbi.nlm.nih.gov/snp/rs200415679/) |
| Variant type | single nucleotide variant |
| Location | chr19:15161025-15161025 (GRCh38) |
| ClinVar | [VCV713631](https://www.ncbi.nlm.nih.gov/clinvar/variation/713631/) |

**All HGVS expressions:** `NC_000019.10:g.15161025G>A`, `NC_000019.9:g.15271836G>A`, `NG_009819.1:g.44957C>T`, `NM_000435.3:c.6603C>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 -4.776, GERP -2.55 — fast-evolving / accelerated position
- CADD: **PHRED 0.513**. 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 **0.00844%** (sas) · FAF95 0.0039% · FAF99 0.00288% · 7/82,954 in the highest group · 63/1,534,748 alleles overall — very rare (popmax 0.00844%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.00844% | 11,851 |
| African / African-American | 0.00681% | 14,687 |
| European (non-Finnish) | 0.00421% | 23,779 |
| East Asian | 0.00239% | 41,882 |
| Admixed American | 0.00195% | 51,332 |
| Remaining individuals (not grpmax-eligible) | 0.00168% | 59,402 |

*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}

**NOTCH3** population constraint: LOEUF 0.566, pLI 1.5089e-07, missense-Z 1.8748. *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):

- **cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1** — Definitive (AD)
- **inherited thrombocytopenia** — Limited (AR)
- **pulmonary arterial hypertension** — Disputed (AD)
- **cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1** — Definitive (AR)

## Protein context {#protein}

Residue **2201** lies in a UniProt-annotated variant site (in carasil1; likely pathogenic); a UniProt-annotated variant site (in lmns; likely pathogenic); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 61.79, 7% of residues very-high.

**6 experimental structure(s)** (PDB): [4ZLP](https://www.rcsb.org/structure/4ZLP), [5CZV](https://www.rcsb.org/structure/5CZV), [5CZX](https://www.rcsb.org/structure/5CZX), [6WQU](https://www.rcsb.org/structure/6WQU), [6XSW](https://www.rcsb.org/structure/6XSW), [8OS0](https://www.rcsb.org/structure/8OS0).

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

*Describes the biological roles of NOTCH3 (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:** NOTCH3's established molecular role includes signaling receptor activity. p.Pro2201= falls in the disordered region. In Reactome, NOTCH3 is annotated in disease pathway(s) including **Defective LFNG causes SCDO3**.

**Disease mechanism (Reactome):** NOTCH3 loss or alteration is curated in [Defective LFNG causes SCDO3](https://reactome.org/content/detail/R-HSA-5083630).

### Pathways affected {#pathways}

NOTCH3 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective LFNG causes SCDO3](https://reactome.org/content/detail/R-HSA-5083630) | curated |
| [Noncanonical activation of NOTCH3](https://reactome.org/content/detail/R-HSA-9017802) | curated |
| [Notch-HLH transcription pathway](https://reactome.org/content/detail/R-HSA-350054) | curated |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | curated |
| [NOTCH3 Activation and Transmission of Signal to the Nucleus](https://reactome.org/content/detail/R-HSA-9013507) | electronic |
| [NOTCH3 Intracellular Domain Regulates Transcription](https://reactome.org/content/detail/R-HSA-9013508) | electronic |
| [Pre-NOTCH Processing in Golgi](https://reactome.org/content/detail/R-HSA-1912420) | electronic |
| [Pre-NOTCH Processing in the Endoplasmic Reticulum](https://reactome.org/content/detail/R-HSA-1912399) | electronic |

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

**Molecular function:** signaling receptor activity, identical protein binding, cadherin binding.

**Biological process:** Notch signaling pathway, positive regulation of miRNA transcription.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-01.

**Submitter consensus:** conflicting (2 Likely benign, 1 Uncertain significance).

**Submission history:** 3 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-10-20 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-01 |

## Associated conditions {#conditions}

[cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1](https://sugi.bio/atlas/disease/cerebral-arteriopathy-autosomal-dominant-with-subcortical-infarcts-and-leukoencephalopathy-type-1/).

**Reported phenotype names (ClinVar):** Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, not provided, not specified, CASIL, Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy 1, CADASIL 1, DEMENTIA, HEREDITARY MULTIINFARCT TYPE, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related NOTCH3 variant pages (same residue, condition, or type): [NOTCH3 c.341-2A>T](/variant/notch3-c-341-minus-2a-t), [NOTCH3 p.Arg1006Cys](/variant/notch3-p-arg1006cys), [NOTCH3 p.Arg1076Cys](/variant/notch3-p-arg1076cys), [NOTCH3 p.Arg110Cys](/variant/notch3-p-arg110cys), [NOTCH3 p.Arg133Cys](/variant/notch3-p-arg133cys), [NOTCH3 p.Arg141Cys](/variant/notch3-p-arg141cys), [NOTCH3 p.Arg153Cys](/variant/notch3-p-arg153cys), [NOTCH3 p.Arg169Cys](/variant/notch3-p-arg169cys).

### 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 713631). 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.*