Is NOTCH3 p.Arg207Cys (c.619C>T) pathogenic?

NOTCH3 p.Arg207Cys (c.619C>T) is classified Pathogenic/Likely pathogenic in NOTCH3 (ClinVar, Multiple submitters, 16 submitters; last evaluated 2025-11-02). AlphaMissense: likely benign (0.2504); Very rare (popmax 0.00223%, eas); Associated with lateral meningocele syndrome.

How common is NOTCH3 p.Arg207Cys (c.619C>T) in the general population?

NOTCH3 p.Arg207Cys (c.619C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about NOTCH3 p.Arg207Cys (c.619C>T)?

AlphaMissense predicts likely benign (score 0.2504) — an in-silico prediction, not a clinical call.

NOTCH3 p.Arg207Cys

Q: What condition is associated with NOTCH3 p.Arg207Cys (c.619C>T)?

NOTCH3 p.Arg207Cys (c.619C>T) is associated with lateral meningocele syndrome, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (ClinVar).

c.619C>T · rs775267348 · VCV447862

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 16 submitters

AlphaMissense

likely benign

0.2504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lateral meningocele syndrome

Computational evidence

Protein change
AlphaMissense	0.2504	likely benign ⚠ discordant with ClinVar
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -6.26	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.8	GERP 0.72, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic
Overall
CADD	21.7	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 0.00223% East Asian · 1/44,874 alleles

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

Overall 0.00062% 10/1,613,076 alleles · very rare exomes 9/1,460,890 · genomes 1/152,186 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,874
Admixed American	0.00167%	59,856
South Asian	0.0011%	91,074
European (non-Finnish)	0.000593%	168,569

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.Arg207Cys
Coding: c.619C>T
MANE Select: NM_000435
dbSNP: rs775267348
Type: single nucleotide variant
Location: chr19:15192020 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 207: the egf-like 5 domain; a UniProt-annotated variant site (in cadasil1)

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

Disease context

lateral meningocele syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 cerebral arteriopathy with subcortical infarcts and leukoencephalopathy myofibromatosis, infantile, 2

Similar variants

NOTCH3 p.Arg207His Uncertain significance ★★ ⚠ same residue
NOTCH3 c.341-2A>T Pathogenic ★★ same condition
NOTCH3 p.Arg1006Cys Pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg1076Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg110Cys Pathogenic ★★ same condition
NOTCH3 p.Arg133Cys Pathogenic/Likely pathogenic ★★ same condition
NOTCH3 p.Arg141Cys Pathogenic ★★ same condition
NOTCH3 p.Arg153Cys Pathogenic ★★ 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-arg207cys (accessed [today's date]).

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