Is NOTCH3 p.Pro42Ser (c.124C>T) pathogenic?

NOTCH3 p.Pro42Ser (c.124C>T) is classified Uncertain significance in NOTCH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-01). AlphaMissense: likely benign (0.0656); Very rare (popmax 0.00334%, amr); Associated with Inborn genetic diseases.

What condition is associated with NOTCH3 p.Pro42Ser (c.124C>T)?

NOTCH3 p.Pro42Ser (c.124C>T) is associated with Inborn genetic diseases (ClinVar).

How common is NOTCH3 p.Pro42Ser (c.124C>T) in the general population?

NOTCH3 p.Pro42Ser (c.124C>T) is very rare (popmax 0.00334%, amr) (gnomAD).

What do computational predictors say about NOTCH3 p.Pro42Ser (c.124C>T)?

AlphaMissense predicts likely benign (score 0.0656) — an in-silico prediction, not a clinical call.

NOTCH3 p.Pro42Ser

c.124C>T · rs372995747 · VCV3201370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0656 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00334%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0656	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -6.51	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 5.3	GERP 0.11, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic
Overall
CADD	14.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00334% Admixed American · 2/59,960 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000434% 7/1,611,590 alleles · very rare exomes 6/1,459,338 · genomes 1/152,252 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00334%	29,980
Remaining individualsnot grpmax-eligible	0.00321%	31,197
South Asian	0.0011%	90,902
European (non-Finnish)	0.00017%	589,894

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.Pro42Ser
Coding: c.124C>T
MANE Select: NM_000435
dbSNP: rs372995747
Type: single nucleotide variant
Location: chr19:15197573 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 42: the egf-like 1 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.Pro42= Likely benign ★ 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-pro42ser (accessed [today's date]).

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