Is NOTCH2 p.Phe244Ser (c.731T>C) pathogenic?

NOTCH2 p.Phe244Ser (c.731T>C) is classified Uncertain significance in NOTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-01). AlphaMissense: ambiguous (0.5224); Very rare (popmax 0.00322%, nfe); Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Phe244Ser (c.731T>C)?

NOTCH2 p.Phe244Ser (c.731T>C) is associated with Alagille syndrome due to a NOTCH2 point mutation, acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Phe244Ser (c.731T>C) in the general population?

NOTCH2 p.Phe244Ser (c.731T>C) is very rare (popmax 0.00322%, nfe) (gnomAD).

What do computational predictors say about NOTCH2 p.Phe244Ser (c.731T>C)?

AlphaMissense predicts ambiguous (score 0.5224) — an in-silico prediction, not a clinical call.

NOTCH2 p.Phe244Ser

c.731T>C · VCV3257156

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5224 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00322%, nfe)

Conditions

Alagille syndrome due to a NOTCH2 point mutation

Computational evidence

Protein change
AlphaMissense	0.5224	ambiguous
REVEL	0.527	indeterminate
SaProt	LLR -9.98	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 46 kb · p 1.7e-32 · regional, not allelic
Overall
CADD	25.4	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 0.00322% European (non-Finnish) · 38/1,179,860 alleles

Filtering AF 0.00239% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0021%

Overall 0.00242% 39/1,613,846 alleles · very rare exomes 37/1,461,604 · genomes 2/152,242 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00322%	31,049
Remaining individualsnot grpmax-eligible	0.0016%	62,464

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.Phe244Ser
Coding: c.731T>C
MANE Select: NM_024408
Type: single nucleotide variant
Location: chr1:119997017 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 244: the egf-like 6 domain

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

Also linked: acroosteolysis dominant type

Similar variants

NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 p.Arg2400Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2223Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2263Ter Pathogenic ★★ same condition
NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same condition
NOTCH2 c.2753-8T>A Uncertain significance ★★ same condition
NOTCH2 c.5214-10A>G Uncertain significance ★★ same condition
NOTCH2 c.874+4T>C 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-phe244ser (accessed [today's date]).

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