Is NOTCH2 p.Arg1607Pro (c.4820G>C) pathogenic?

NOTCH2 p.Arg1607Pro (c.4820G>C) is classified Uncertain significance in NOTCH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-13). AlphaMissense: likely benign (0.1363); Very rare (popmax 0.000593%, nfe); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Arg1607Pro (c.4820G>C)?

NOTCH2 p.Arg1607Pro (c.4820G>C) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Arg1607Pro (c.4820G>C) in the general population?

NOTCH2 p.Arg1607Pro (c.4820G>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about NOTCH2 p.Arg1607Pro (c.4820G>C)?

AlphaMissense predicts likely benign (score 0.1363) — an in-silico prediction, not a clinical call.

NOTCH2 p.Arg1607Pro

c.4820G>C · rs372710038 · VCV2783869

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1363 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
AlphaMissense	0.1363	likely benign
REVEL	0.51	indeterminate
SaProt	LLR -8.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 40 kb · p 1.4e-18 · regional, not allelic
Overall
CADD	24.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000593% European (non-Finnish) · 7/1,180,022 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,614,138 alleles · very rare exomes 7/1,461,850 · genomes 0/152,288 · 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: NOTCH2
Protein: p.Arg1607Pro
Coding: c.4820G>C
MANE Select: NM_024408
dbSNP: rs372710038
Type: single nucleotide variant
Location: chr1:119923676 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 1607: the 'negative regulatory region (nrr)' region

Full NOTCH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

acroosteolysis dominant type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH2 p.Arg1607His Uncertain significance ★ ⚠ same residue
NOTCH2 p.Arg1607Ser 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-arg1607pro (accessed [today's date]).

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