Is NOTCH1 p.Pro2517Ser (c.7549C>T) pathogenic?

NOTCH1 p.Pro2517Ser (c.7549C>T) is classified Uncertain significance in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-22). AlphaMissense: ambiguous (0.5197); Very rare (popmax 8.48e-05%, nfe); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Pro2517Ser (c.7549C>T)?

NOTCH1 p.Pro2517Ser (c.7549C>T) is associated with Adams-Oliver syndrome 5 (ClinVar).

How common is NOTCH1 p.Pro2517Ser (c.7549C>T) in the general population?

NOTCH1 p.Pro2517Ser (c.7549C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about NOTCH1 p.Pro2517Ser (c.7549C>T)?

AlphaMissense predicts ambiguous (score 0.5197) — an in-silico prediction, not a clinical call.

NOTCH1 p.Pro2517Ser

c.7549C>T · rs2133314214 · VCV1998000

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5197 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

Adams-Oliver syndrome 5

Computational evidence

Protein change
AlphaMissense	0.5197	ambiguous
REVEL	0.598	indeterminate
SaProt	LLR -5.78	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 272 bp · p 0.00026 · regional, not allelic
Overall
CADD	26.6	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 8.48e-05% European (non-Finnish) · 1/1,179,264 alleles

Overall 6.86e-05% 1/1,457,914 alleles · very rare

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: NOTCH1
Protein: p.Pro2517Ser
Coding: c.7549C>T
MANE Select: NM_017617
dbSNP: rs2133314214
Type: single nucleotide variant
Location: chr9:136496190 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 2517: the 'disordered' region

Full NOTCH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Adams-Oliver syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH1 p.Pro2517Ala Uncertain significance ★ same residue
NOTCH1 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 c.3511-1G>A Likely pathogenic ★★ same condition
NOTCH1 p.Arg1107Ter Pathogenic ★★ same condition
NOTCH1 p.Arg448Ter Pathogenic ★★ same condition
NOTCH1 p.Arg56Ter Pathogenic ★★ same condition
NOTCH1 p.Asp1517Asn Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 p.Cys1496Tyr Pathogenic/Likely pathogenic ★★ 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/notch1-p-pro2517ser (accessed [today's date]).

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