Is NOTCH1 p.Pro110Ser (c.328C>T) pathogenic?

NOTCH1 p.Pro110Ser (c.328C>T) is classified Uncertain significance in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-20). AlphaMissense: ambiguous (0.5576); Very rare (popmax 8.48e-05%, nfe).

How common is NOTCH1 p.Pro110Ser (c.328C>T) in the general population?

NOTCH1 p.Pro110Ser (c.328C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about NOTCH1 p.Pro110Ser (c.328C>T)?

AlphaMissense predicts ambiguous (score 0.5576) — an in-silico prediction, not a clinical call.

NOTCH1 p.Pro110Ser

c.328C>T · rs1064796976 · VCV424457

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5576 · ACMG-weighted

gnomAD v4.1

Rare

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

Computational evidence

Protein change
AlphaMissense	0.5576	ambiguous
REVEL	0.519	indeterminate
SaProt	LLR -7.12	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP -0.62, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 27 kb · p 4.1e-08 · regional, not allelic
Overall
CADD	27.8	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) · 1/1,179,650 alleles

Overall 6.2e-05% 1/1,611,858 alleles · very rare exomes 1/1,459,514 · genomes 0/152,344 · 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: NOTCH1
Protein: p.Pro110Ser
Coding: c.328C>T
MANE Select: NM_017617
dbSNP: rs1064796976
Type: single nucleotide variant
Location: chr9:136523792 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 110: the egf-like 3 domain

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

Similar variants

NOTCH1 p.Pro110Leu Conflicting classifications of pathogenicity ★ same residue
NOTCH1 p.Pro110= Likely benign ★ same residue
NOTCH1 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same type
NOTCH1 c.1904-2A>G Pathogenic/Likely pathogenic ★★ same type
NOTCH1 c.3511-1G>A Likely pathogenic ★★ same type
NOTCH1 p.Arg1107Ter Pathogenic ★★ same type
NOTCH1 p.Arg448Ter Pathogenic ★★ same type
NOTCH1 p.Arg56Ter Pathogenic ★★ same type

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-pro110ser (accessed [today's date]).

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