Is NOTCH2 p.Ala862Val (c.2585C>T) pathogenic?

NOTCH2 p.Ala862Val (c.2585C>T) is classified Benign/Likely benign in NOTCH2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0874); Rare (popmax 0.762%, afr); Associated with acroosteolysis dominant type.

What condition is associated with NOTCH2 p.Ala862Val (c.2585C>T)?

NOTCH2 p.Ala862Val (c.2585C>T) is associated with acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Ala862Val (c.2585C>T) in the general population?

NOTCH2 p.Ala862Val (c.2585C>T) is rare (popmax 0.762%, afr) (gnomAD).

What do computational predictors say about NOTCH2 p.Ala862Val (c.2585C>T)?

AlphaMissense predicts likely benign (score 0.0874) — an in-silico prediction, not a clinical call.

NOTCH2 p.Ala862Val

c.2585C>T · rs35656321 · VCV134963

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0874 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.762%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

acroosteolysis dominant type

Computational evidence

Protein change
AlphaMissense	0.0874	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -6.78	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 40 kb · p 1.4e-18 · regional, not allelic
Overall
CADD	27.0	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

Grpmax group 0.762% African / African-American · 572/75,044 alleles

Filtering AF 0.71% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.69%

Overall 0.0416% 671/1,614,184 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.762%	131
Admixed American	0.07%	1,429
Middle Eastern	0.066%	1,516
Remaining individualsnot grpmax-eligible	0.0512%	1,953
South Asian	0.00549%	18,217
European (non-Finnish)	0.00136%	73,751

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.Ala862Val
Coding: c.2585C>T
MANE Select: NM_024408
dbSNP: rs35656321
Type: single nucleotide variant
Location: chr1:119949021 (GRCh38)
Gene constraint: LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 59.51 · 2 PDB
Residue 862: a disulfide bond; the egf-like 22 domain

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.Ala862Ser 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
NOTCH2 c.5214-10A>G 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-ala862val (accessed [today's date]).

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