Is NOTCH3 p.Met1663Val (c.4987A>G) pathogenic?

NOTCH3 p.Met1663Val (c.4987A>G) is classified Conflicting classifications of pathogenicity in NOTCH3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-09-19). AlphaMissense: likely benign (0.0796); Ultra-rare (popmax 0.0134%, eas); Associated with Inborn genetic diseases.

What condition is associated with NOTCH3 p.Met1663Val (c.4987A>G)?

NOTCH3 p.Met1663Val (c.4987A>G) is associated with Inborn genetic diseases (ClinVar).

How common is NOTCH3 p.Met1663Val (c.4987A>G) in the general population?

NOTCH3 p.Met1663Val (c.4987A>G) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about NOTCH3 p.Met1663Val (c.4987A>G)?

AlphaMissense predicts likely benign (score 0.0796) — an in-silico prediction, not a clinical call.

NOTCH3 p.Met1663Val

c.4987A>G · rs771114489 · VCV3201375

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0796 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0796	likely benign
REVEL	0.204	benign-leaning
SaProt	LLR -4.48	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 0.93	GERP -0.69, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 16 kb · p 4.8e-09 · regional, not allelic
Overall
CADD	17.64	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 0.0134% East Asian · 6/44,872 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00087% 14/1,609,544 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,479
Remaining individualsnot grpmax-eligible	0.0064%	15,614
South Asian	0.00439%	22,770

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.Met1663Val
Coding: c.4987A>G
MANE Select: NM_000435
dbSNP: rs771114489
Type: single nucleotide variant
Location: chr19:15170458 (GRCh38)
Gene constraint: LOEUF 0.566 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.79 · 6 PDB
Residue 1663: a UniProt-annotated variant site (in carasil1; likely pathogenic); an α-helix

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.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
NOTCH3 p.Ala980Ser 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-met1663val (accessed [today's date]).

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