Is NOTCH3 p.Pro167Ser (c.499C>T) pathogenic?

NOTCH3 p.Pro167Ser (c.499C>T) is classified Benign in NOTCH3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.12); Rare (popmax 0.372%, eas); Associated with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy.

What condition is associated with NOTCH3 p.Pro167Ser (c.499C>T)?

NOTCH3 p.Pro167Ser (c.499C>T) is associated with cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (ClinVar).

How common is NOTCH3 p.Pro167Ser (c.499C>T) in the general population?

NOTCH3 p.Pro167Ser (c.499C>T) is rare (popmax 0.372%, eas) (gnomAD).

What do computational predictors say about NOTCH3 p.Pro167Ser (c.499C>T)?

AlphaMissense predicts likely benign (score 0.12) — an in-silico prediction, not a clinical call.

NOTCH3 p.Pro167Ser

c.499C>T · rs202157633 · VCV767211

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.12 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.372%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebral arteriopathy with subcortical infarcts and leukoencephalopathy

Computational evidence

Protein change
AlphaMissense	0.12	likely benign
REVEL	0.274	benign-leaning
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.32	donor gain · deltas
Constraint at this position
Conservation	phyloP 2.4	GERP 1.9, phastCons 0.99
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic
Overall
CADD	16.91	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 0.372% East Asian · 167/44,876 alleles

Filtering AF 0.326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.308%

Overall 0.011% 178/1,612,956 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.372%	269
Remaining individualsnot grpmax-eligible	0.0176%	5,681

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.Pro167Ser
Coding: c.499C>T
MANE Select: NM_000435
dbSNP: rs202157633
Type: single nucleotide variant
Location: chr19:15192140 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 167: the egf-like 4; calcium-binding domain; a disulfide bond

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

Disease context

cerebral arteriopathy with subcortical infarcts and leukoencephalopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NOTCH3 p.Pro167= Likely benign ★ same residue
NOTCH3 p.Arg207Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg544Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg54Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Arg578Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
NOTCH3 p.Cys194Tyr Pathogenic ★★ same condition
NOTCH3 p.Cys233Tyr Pathogenic/Likely pathogenic ★★ same condition
NOTCH3 p.Asp45His 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-pro167ser (accessed [today's date]).

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