Is NOTCH2 p.Ala3Val (c.8C>T) pathogenic?

NOTCH2 p.Ala3Val (c.8C>T) is classified Likely benign in NOTCH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-20). AlphaMissense: likely benign (0.2276); Very rare (popmax 0.00234%, sas); Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Ala3Val (c.8C>T)?

NOTCH2 p.Ala3Val (c.8C>T) is associated with Alagille syndrome due to a NOTCH2 point mutation (ClinVar).

How common is NOTCH2 p.Ala3Val (c.8C>T) in the general population?

NOTCH2 p.Ala3Val (c.8C>T) is very rare (popmax 0.00234%, sas) (gnomAD).

What do computational predictors say about NOTCH2 p.Ala3Val (c.8C>T)?

AlphaMissense predicts likely benign (score 0.2276) — an in-silico prediction, not a clinical call.

NOTCH2 p.Ala3Val

c.8C>T · rs200646249 · VCV1301776

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2276 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00234%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Alagille syndrome due to a NOTCH2 point mutation

Computational evidence

Protein change
AlphaMissense	0.2276	likely benign
REVEL	0.319	indeterminate
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 68 bp · p 0.32 · regional, not allelic
Overall
CADD	18.44	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

Grpmax group 0.00234% South Asian · 2/85,294 alleles

Filtering AF 0.00117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000992%

Overall 0.00155% 24/1,547,598 alleles · very rare exomes 21/1,395,508 · genomes 3/152,090 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00234%	42,647
European (non-Finnish)	0.00182%	54,990
African / African-American	0.00138%	72,472

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.Ala3Val
Coding: c.8C>T
MANE Select: NM_024408
dbSNP: rs200646249
Type: single nucleotide variant
Location: chr1:120069399 (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.Ala3Ser Benign/Likely benign ★★ same residue
NOTCH2 p.Ala3Gly Uncertain significance ★ ⚠ same residue
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

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-ala3val (accessed [today's date]).

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