Is NOTCH3 p.Cys910Tyr (c.2729G>A) pathogenic?

NOTCH3 p.Cys910Tyr (c.2729G>A) is classified Uncertain significance in NOTCH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-20). AlphaMissense: likely pathogenic (0.9916); Very rare (popmax 0.000959%, nfe).

How common is NOTCH3 p.Cys910Tyr (c.2729G>A) in the general population?

NOTCH3 p.Cys910Tyr (c.2729G>A) is very rare (popmax 0.000959%, nfe) (gnomAD).

What do computational predictors say about NOTCH3 p.Cys910Tyr (c.2729G>A)?

AlphaMissense predicts likely pathogenic (score 0.9916) — an in-silico prediction, not a clinical call.

NOTCH3 p.Cys910Tyr

c.2729G>A · VCV4689203

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9916 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000959%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9916	likely pathogenic · top 7% in NOTCH3
REVEL	0.968	strongly pathogenic-leaning
SaProt	LLR -12.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 8,846 bp · p 0.11 · regional, not allelic
Overall
CADD	26.5	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

Grpmax group 0.000959% European (non-Finnish) · 11/1,147,416 alleles

Filtering AF 0.000514% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000376%

Overall 0.000709% 11/1,551,674 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NOTCH3
Protein: p.Cys910Tyr
Coding: c.2729G>A
MANE Select: NM_000435
Type: single nucleotide variant
Location: chr19:15181639 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 910: a disulfide bond; a UniProt-annotated variant site (in carasil1; likely pathogenic); the egf-like 23; calcium-binding domain

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

Similar variants

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
NOTCH3 p.Arg153Cys 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-cys910tyr (accessed [today's date]).

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