Is NOTCH3 p.Ser105Pro (c.313T>C) pathogenic?

NOTCH3 p.Ser105Pro (c.313T>C) is classified Uncertain significance in NOTCH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-05). AlphaMissense: likely pathogenic (0.686); Absent from gnomAD v4.1.

How common is NOTCH3 p.Ser105Pro (c.313T>C) in the general population?

NOTCH3 p.Ser105Pro (c.313T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH3 p.Ser105Pro (c.313T>C)?

AlphaMissense predicts likely pathogenic (score 0.686) — an in-silico prediction, not a clinical call.

NOTCH3 p.Ser105Pro

c.313T>C · rs2145443100 · VCV1720075

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.686 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.686	likely pathogenic
REVEL	0.626	indeterminate
SaProt	LLR -12.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.5, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOTCH3
Protein: p.Ser105Pro
Coding: c.313T>C
MANE Select: NM_000435
dbSNP: rs2145443100
Type: single nucleotide variant
Location: chr19:15192404 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 105: a disulfide bond; the egf-like 2 domain

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

Similar variants

NOTCH3 p.Ser105= Likely benign ★ same residue
NOTCH3 c.341-2A>G Pathogenic ★★ same type
NOTCH3 c.341-2A>T Pathogenic ★★ same type
NOTCH3 p.Arg1006Cys Pathogenic ★★ ⚠ same type
NOTCH3 p.Arg1076Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
NOTCH3 p.Arg110Cys Pathogenic ★★ same type
NOTCH3 p.Arg133Cys Pathogenic/Likely pathogenic ★★ same type
NOTCH3 p.Arg141Cys Pathogenic ★★ same type

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-ser105pro (accessed [today's date]).

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