Is NOTCH2 p.Val1925= (c.5775C>T) pathogenic?

NOTCH2 p.Val1925= (c.5775C>T) is classified Likely benign in NOTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-09-20). Ultra-rare (popmax 0.0201%, mid); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Val1925= (c.5775C>T)?

NOTCH2 p.Val1925= (c.5775C>T) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Val1925= (c.5775C>T) in the general population?

NOTCH2 p.Val1925= (c.5775C>T) is ultra-rare (popmax 0.0201%, mid) (gnomAD).

NOTCH2 p.Val1925=

c.5775C>T · rs368986104 · VCV1126250

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, mid)

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.93 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.4	phastCons 1
Overall
CADD	7.118	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% Middle Eastern · 1/4,984 alleles

Filtering AF 0.00639% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00592%

Overall 0.0059% 95/1,611,228 alleles · ultra-rare exomes 89/1,459,000 · genomes 6/152,228 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0201%	4,984
European (non-Finnish)	0.00771%	12,966
Remaining individualsnot grpmax-eligible	0.00321%	31,187
African / African-American	0.00134%	74,904

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.Val1925=
Coding: c.5775C>T
MANE Select: NM_024408
dbSNP: rs368986104
Type: single nucleotide variant
Location: chr1:119919318 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB

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.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
NOTCH2 c.5214-10A>G Uncertain significance ★★ same condition
NOTCH2 c.874+4T>C 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-val1925 (accessed [today's date]).

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