Is NOTCH2 p.Arg2003Gln (c.6008G>A) pathogenic?

NOTCH2 p.Arg2003Gln (c.6008G>A) is classified Uncertain significance in NOTCH2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-04-08). AlphaMissense: ambiguous (0.4025); Ultra-rare (popmax 0.0512%, eas); Associated with Alagille syndrome due to a NOTCH2 point mutation.

What condition is associated with NOTCH2 p.Arg2003Gln (c.6008G>A)?

NOTCH2 p.Arg2003Gln (c.6008G>A) is associated with Alagille syndrome due to a NOTCH2 point mutation, acroosteolysis dominant type (ClinVar).

How common is NOTCH2 p.Arg2003Gln (c.6008G>A) in the general population?

NOTCH2 p.Arg2003Gln (c.6008G>A) is ultra-rare (popmax 0.0512%, eas) (gnomAD).

What do computational predictors say about NOTCH2 p.Arg2003Gln (c.6008G>A)?

AlphaMissense predicts ambiguous (score 0.4025) — an in-silico prediction, not a clinical call.

NOTCH2 p.Arg2003Gln

c.6008G>A · rs142978073 · VCV1372284

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4025 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0512%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Alagille syndrome due to a NOTCH2 point mutation

Computational evidence

Protein change
AlphaMissense	0.4025	ambiguous
REVEL	0.228	benign-leaning
SaProt	LLR -8.44	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 2,948 bp · p 1.3e-15 · regional, not allelic
Overall
CADD	26.3	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 0.0512% East Asian · 23/44,880 alleles

Filtering AF 0.035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0296%

Overall 0.00223% 36/1,612,972 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0512%	1,951
Remaining individualsnot grpmax-eligible	0.0016%	62,476
African / African-American	0.00133%	75,026
South Asian	0.0011%	91,054
European (non-Finnish)	0.000848%	117,914

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.Arg2003Gln
Coding: c.6008G>A
MANE Select: NM_024408
dbSNP: rs142978073
Type: single nucleotide variant
Location: chr1:119917684 (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

Alagille syndrome due to a NOTCH2 point mutation — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: acroosteolysis dominant type

Similar variants

NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same residue
NOTCH2 p.Arg2003Gly Uncertain significance ★ ⚠ same residue
NOTCH2 p.Arg2003= Likely benign ★ same residue
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-arg2003gln (accessed [today's date]).

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