Is NOTCH2 p.Pro404Leu (c.1211C>T) pathogenic?

NOTCH2 p.Pro404Leu (c.1211C>T) is classified Pathogenic in NOTCH2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-06-07). AlphaMissense: likely benign (0.2608); Absent from gnomAD v4.1; Associated with keratoacanthoma.

What condition is associated with NOTCH2 p.Pro404Leu (c.1211C>T)?

NOTCH2 p.Pro404Leu (c.1211C>T) is associated with keratoacanthoma (ClinVar).

How common is NOTCH2 p.Pro404Leu (c.1211C>T) in the general population?

NOTCH2 p.Pro404Leu (c.1211C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH2 p.Pro404Leu (c.1211C>T)?

AlphaMissense predicts likely benign (score 0.2608) — an in-silico prediction, not a clinical call.

NOTCH2 p.Pro404Leu

c.1211C>T · rs2101145406 · VCV1344880

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2608 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

keratoacanthoma

Computational evidence

Protein change
AlphaMissense	0.2608	likely benign ⚠ discordant with ClinVar
REVEL	0.806	moderately pathogenic-leaning
SaProt	LLR -6.44	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 46 kb · p 1.7e-32 · regional, not allelic
Overall
CADD	25.8	PHRED · no single calibrated threshold — expert panels disagree

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: NOTCH2
Protein: p.Pro404Leu
Coding: c.1211C>T
MANE Select: NM_024408
dbSNP: rs2101145406
Type: single nucleotide variant
Location: chr1:119968130 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 404: a disulfide bond; the egf-like 10 domain

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

Disease context

keratoacanthoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH2 p.Asp415Asn Uncertain significance ★ ⚠ same condition
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-pro404leu (accessed [today's date]).

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