Is NOTCH2 p.Ser2172= (c.6516C>T) pathogenic?

NOTCH2 p.Ser2172= (c.6516C>T) is classified Benign/Likely benign in NOTCH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-03-07). Rare (popmax 0.17%, sas); Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Ser2172= (c.6516C>T)?

NOTCH2 p.Ser2172= (c.6516C>T) is associated with Alagille syndrome due to a NOTCH2 point mutation, acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Ser2172= (c.6516C>T) in the general population?

NOTCH2 p.Ser2172= (c.6516C>T) is rare (popmax 0.17%, sas) (gnomAD).

NOTCH2 p.Ser2172=

c.6516C>T · rs587733506 · VCV598276

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.17%, sas)

Conditions

Alagille syndrome due to a NOTCH2 point mutation

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	phastCons 1
Overall
CADD	5.753	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.17% South Asian · 155/91,088 alleles

Filtering AF 0.148% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.14%

Overall 0.011% 178/1,614,226 alleles · rare exomes 168/1,461,894 · genomes 10/152,332 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.17%	588
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)	0.00169%	59,002

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.Ser2172=
Coding: c.6516C>T
MANE Select: NM_024408
dbSNP: rs587733506
Type: single nucleotide variant
Location: chr1:119916206 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 2172: a UniProt-annotated variant site (in hjcys)

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.Ser2172Thr Uncertain significance ★ ⚠ same residue
NOTCH2 p.Ser2172Tyr Uncertain significance ★ same residue
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

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-ser2172 (accessed [today's date]).

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