Is NOTCH1 p.Pro574Ser (c.1720C>T) pathogenic?

NOTCH1 p.Pro574Ser (c.1720C>T) is classified Uncertain significance in NOTCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-23). AlphaMissense: ambiguous (0.5425); Absent from gnomAD v4.1; Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Pro574Ser (c.1720C>T)?

NOTCH1 p.Pro574Ser (c.1720C>T) is associated with Adams-Oliver syndrome 5 (ClinVar).

How common is NOTCH1 p.Pro574Ser (c.1720C>T) in the general population?

NOTCH1 p.Pro574Ser (c.1720C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH1 p.Pro574Ser (c.1720C>T)?

AlphaMissense predicts ambiguous (score 0.5425) — an in-silico prediction, not a clinical call.

NOTCH1 p.Pro574Ser

c.1720C>T · VCV3703319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5425 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Adams-Oliver syndrome 5

Computational evidence

Protein change
AlphaMissense	0.5425	ambiguous
REVEL	0.768	pathogenic-leaning
SaProt	LLR -7.25	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 2,211 bp · p 2.3e-06 · regional, not allelic
Overall
CADD	26.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOTCH1
Protein: p.Pro574Ser
Coding: c.1720C>T
MANE Select: NM_017617
Type: single nucleotide variant
Location: chr9:136515666 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 574: a disulfide bond; the egf-like 15; calcium-binding 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.Pro574Leu Likely benign ★ ⚠ same residue
NOTCH1 p.Pro574= 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-pro574ser (accessed [today's date]).

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