Is NOTCH2 p.Cys19= (c.57C>T) pathogenic?

NOTCH2 p.Cys19= (c.57C>T) is classified Likely benign in NOTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-07-01). Ultra-rare (popmax 0.0521%, nfe).

How common is NOTCH2 p.Cys19= (c.57C>T) in the general population?

NOTCH2 p.Cys19= (c.57C>T) is ultra-rare (popmax 0.0521%, nfe) (gnomAD).

NOTCH2 p.Cys19=

c.57C>T · rs11810554 · VCV1013526

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0521%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.138	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	phastCons 1
Overall
CADD	10.76	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0521% European (non-Finnish) · 608/1,166,982 alleles

Filtering AF 0.0487% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0472%

Overall 0.0433% 679/1,569,168 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0574%	1,742
European (non-Finnish)grpmax	0.0521%	1,919
Admixed American	0.0487%	2,054
Middle Eastern	0.0216%	4,622
African / African-American	0.00678%	14,747
East Asian	0.00231%	43,236
Finnishnot grpmax-eligible	0.00216%	46,226

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: NOTCH2
Protein: p.Cys19=
Coding: c.57C>T
MANE Select: NM_024408
dbSNP: rs11810554
Type: single nucleotide variant
Location: chr1:120069350 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NOTCH2 p.Cys19Trp Benign ★★ same residue
NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same type
NOTCH2 p.Arg2400Ter Pathogenic ★★ same type
NOTCH2 p.Gln2223Ter Pathogenic ★★ same type
NOTCH2 p.Gln2263Ter Pathogenic ★★ same type
NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same type
NOTCH2 c.2753-8T>A Uncertain significance ★★ same type
NOTCH2 c.5214-10A>G Uncertain significance ★★ 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/notch2-p-cys19 (accessed [today's date]).

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