Is NOTCH3 p.Arg985Pro (c.2954G>C) pathogenic?

NOTCH3 p.Arg985Pro (c.2954G>C) is classified Uncertain significance in NOTCH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely benign (0.2175); Very rare (popmax 8.52e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with NOTCH3 p.Arg985Pro (c.2954G>C)?

NOTCH3 p.Arg985Pro (c.2954G>C) is associated with Inborn genetic diseases (ClinVar).

How common is NOTCH3 p.Arg985Pro (c.2954G>C) in the general population?

NOTCH3 p.Arg985Pro (c.2954G>C) is very rare (popmax 8.52e-05%, nfe) (gnomAD).

What do computational predictors say about NOTCH3 p.Arg985Pro (c.2954G>C)?

AlphaMissense predicts likely benign (score 0.2175) — an in-silico prediction, not a clinical call.

NOTCH3 p.Arg985Pro

c.2954G>C · VCV4121705

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2175 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.52e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2175	likely benign
REVEL	0.552	indeterminate
SaProt	LLR -13.14	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.4	GERP -3.1
Regional constraint	o/e 0.95	unconstrained · MANE · 8,846 bp · p 0.11 · regional, not allelic
Overall
CADD	19.14	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 8.52e-05% European (non-Finnish) · 1/1,173,164 alleles

Overall 6.26e-05% 1/1,597,646 alleles · very rare exomes 1/1,445,330 · genomes 0/152,316 · 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: NOTCH3
Protein: p.Arg985Pro
Coding: c.2954G>C
MANE Select: NM_000435
Type: single nucleotide variant
Location: chr19:15181001 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 985: a UniProt-annotated variant site (in carasil1; likely pathogenic); a UniProt-annotated variant site (in cadasil1); the egf-like 25 domain

Full NOTCH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH3 p.Arg985Cys Pathogenic/Likely pathogenic ★★ ⚠ same residue
NOTCH3 p.Trp1003Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Ala102Ser Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala1044Ser Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala1917Val Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala2256Ser Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala906Val Uncertain significance ★★ ⚠ same condition
NOTCH3 p.Ala979Thr 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/notch3-p-arg985pro (accessed [today's date]).

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