Is NOTCH1 p.Pro67Ser (c.199C>T) pathogenic?

NOTCH1 p.Pro67Ser (c.199C>T) is classified Uncertain significance in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-17). AlphaMissense: likely benign (0.3106); Very rare (popmax 8.53e-05%, nfe); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Pro67Ser (c.199C>T)?

NOTCH1 p.Pro67Ser (c.199C>T) is associated with Adams-Oliver syndrome 5 (ClinVar).

How common is NOTCH1 p.Pro67Ser (c.199C>T) in the general population?

NOTCH1 p.Pro67Ser (c.199C>T) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about NOTCH1 p.Pro67Ser (c.199C>T)?

AlphaMissense predicts likely benign (score 0.3106) — an in-silico prediction, not a clinical call.

NOTCH1 p.Pro67Ser

c.199C>T · rs2133379665 · VCV2127816

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3106 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Adams-Oliver syndrome 5

Computational evidence

Protein change
AlphaMissense	0.3106	likely benign
REVEL	0.309	indeterminate
SaProt	LLR -14.88	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 27 kb · p 4.1e-08 · regional, not allelic
Overall
CADD	26.1	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 8.53e-05% European (non-Finnish) · 1/1,172,302 alleles

Overall 6.26e-05% 1/1,596,746 alleles · very rare exomes 1/1,444,418 · genomes 0/152,328 · 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.Pro67Ser
Coding: c.199C>T
MANE Select: NM_017617
dbSNP: rs2133379665
Type: single nucleotide variant
Location: chr9:136523921 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 67: the egf-like 2 domain

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.Pro67Leu Uncertain significance ★ ⚠ same residue
NOTCH1 p.Pro67= Likely benign ★ 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

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-pro67ser (accessed [today's date]).

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