Is NOTCH2 p.Ala7Ser (c.19G>T) pathogenic?

NOTCH2 p.Ala7Ser (c.19G>T) is classified Uncertain significance in NOTCH2 (ClinVar, Single submitter, 1 submitter). AlphaMissense: likely benign (0.1243); Very rare (popmax 0.00362%, amr); Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Ala7Ser (c.19G>T)?

NOTCH2 p.Ala7Ser (c.19G>T) is associated with Alagille syndrome due to a NOTCH2 point mutation (ClinVar).

How common is NOTCH2 p.Ala7Ser (c.19G>T) in the general population?

NOTCH2 p.Ala7Ser (c.19G>T) is very rare (popmax 0.00362%, amr) (gnomAD).

What do computational predictors say about NOTCH2 p.Ala7Ser (c.19G>T)?

AlphaMissense predicts likely benign (score 0.1243) — an in-silico prediction, not a clinical call.

NOTCH2 p.Ala7Ser

c.19G>T · rs2101452527 · VCV3234952

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00362%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Alagille syndrome due to a NOTCH2 point mutation

Computational evidence

Protein change
AlphaMissense	0.1243	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -6.79	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 3.8	phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 68 bp · p 0.32 · regional, not allelic
Overall
CADD	18.2	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

Grpmax group 0.00362% Admixed American · 2/55,308 alleles

Filtering AF 0.0006% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000224%

Overall 0.000128% 2/1,556,560 alleles · very rare exomes 2/1,404,572 · genomes 0/151,988 · joint denominator

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.Ala7Ser
Coding: c.19G>T
MANE Select: NM_024408
dbSNP: rs2101452527
Type: single nucleotide variant
Location: chr1:120069388 (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

Disease context

Alagille syndrome due to a NOTCH2 point mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH2 p.Arg2400Ter Pathogenic ★★ same condition
NOTCH2 c.5214-10A>G Uncertain significance ★★ same condition
NOTCH2 p.Ala1154Val Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Ala1340Val Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Ala1797Val Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Ala2018Ser Uncertain significance ★★ same condition
NOTCH2 p.Ala2198Thr Uncertain significance ★★ ⚠ same condition
NOTCH2 p.Ala2333Val 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/notch2-p-ala7ser (accessed [today's date]).

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