Is NOTCH3 p.Pro2091Ser (c.6271C>T) pathogenic?

NOTCH3 p.Pro2091Ser (c.6271C>T) is classified Uncertain significance in NOTCH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely benign (0.0792); No allele count reported in gnomAD v4.1 (AN 1,524,900); Associated with Inborn genetic diseases.

What condition is associated with NOTCH3 p.Pro2091Ser (c.6271C>T)?

NOTCH3 p.Pro2091Ser (c.6271C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NOTCH3 p.Pro2091Ser (c.6271C>T) in the general population?

NOTCH3 p.Pro2091Ser (c.6271C>T) is no allele count reported in gnomAD v4.1 (AN 1,524,900) (gnomAD).

What do computational predictors say about NOTCH3 p.Pro2091Ser (c.6271C>T)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

NOTCH3 p.Pro2091Ser

c.6271C>T · VCV4626310

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,524,900)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.107	moderately benign-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP -1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 947 bp · p 0.67 · regional, not allelic
Overall
CADD	17.46	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,524,900). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: NOTCH3
Protein: p.Pro2091Ser
Coding: c.6271C>T
MANE Select: NM_000435
Type: single nucleotide variant
Location: chr19:15161357 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 2091: a UniProt-annotated variant site (in carasil1; likely pathogenic); a UniProt-annotated variant site (in lmns; likely pathogenic); the 'disordered' region

Full NOTCH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH3 p.Trp1003Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Ala102Ser Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala1044Ser Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala1917Val Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala2256Ser Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala906Val Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala979Thr Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala980Ser Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/notch3-p-pro2091ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown