Is NOTCH3 p.Cys511Ser (c.1531T>A) pathogenic?

NOTCH3 p.Cys511Ser (c.1531T>A) is classified Conflicting classifications of pathogenicity in NOTCH3 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-03-02). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1.

How common is NOTCH3 p.Cys511Ser (c.1531T>A) in the general population?

NOTCH3 p.Cys511Ser (c.1531T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NOTCH3 p.Cys511Ser (c.1531T>A)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

NOTCH3 p.Cys511Ser

c.1531T>A · rs2046897246 · VCV2684131

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic · top 2% in NOTCH3
REVEL	0.948	strongly pathogenic-leaning
SaProt	LLR -12.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.7, phastCons 1
Regional constraint	o/e 0.78	unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic
Overall
CADD	27.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NOTCH3
Protein: p.Cys511Ser
Coding: c.1531T>A
MANE Select: NM_000435
dbSNP: rs2046897246
Type: single nucleotide variant
Location: chr19:15187956 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 511: the egf-like 13; calcium-binding domain; a UniProt-annotated variant site (in cadasil1); a disulfide bond

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

Similar variants

NOTCH3 p.Cys511Arg Pathogenic/Likely pathogenic ★★ same residue
NOTCH3 p.Cys511Gly Pathogenic ★ same residue
NOTCH3 p.Cys511Trp Pathogenic ★ same residue
NOTCH3 p.Cys511Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH3 c.341-2A>G Pathogenic ★★ same type
NOTCH3 c.341-2A>T Pathogenic ★★ same type
NOTCH3 p.Arg1006Cys Pathogenic ★★ ⚠ same type
NOTCH3 p.Arg1076Cys Pathogenic/Likely pathogenic ★★ ⚠ same type

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-cys511ser (accessed [today's date]).

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