Is NOTCH1 p.Ser2136= (c.6408G>A) pathogenic?

NOTCH1 p.Ser2136= (c.6408G>A) is classified Likely benign in NOTCH1 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2024-12-27). Very rare (popmax 0.00834%, amr); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Ser2136= (c.6408G>A)?

NOTCH1 p.Ser2136= (c.6408G>A) is associated with Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection, aortic valve disease 1 (ClinVar).

How common is NOTCH1 p.Ser2136= (c.6408G>A) in the general population?

NOTCH1 p.Ser2136= (c.6408G>A) is very rare (popmax 0.00834%, amr) (gnomAD).

NOTCH1 p.Ser2136=

c.6408G>A · rs933773128 · VCV1129171

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00834%, amr)

Conditions

Adams-Oliver syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -14	GERP -4.5
Overall
CADD	0.064	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00834% Admixed American · 5/59,934 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00181% 29/1,606,122 alleles · very rare exomes 26/1,453,874 · genomes 3/152,248 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00834%	11,987
European (non-Finnish)	0.00195%	51,278
South Asian	0.0011%	91,014

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: NOTCH1
Protein: p.Ser2136=
Coding: c.6408G>A
MANE Select: NM_017617
dbSNP: rs933773128
Type: single nucleotide variant
Location: chr9:136497331 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB

Full NOTCH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Adams-Oliver syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: familial thoracic aortic aneurysm and aortic dissection aortic valve disease 1

Similar variants

NOTCH1 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 c.3511-1G>A Likely pathogenic ★★ same condition
NOTCH1 p.Arg1107Ter Pathogenic ★★ same condition
NOTCH1 p.Arg448Ter Pathogenic ★★ same condition
NOTCH1 p.Arg56Ter Pathogenic ★★ same condition
NOTCH1 p.Asp1517Asn Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 p.Cys1496Tyr Pathogenic/Likely pathogenic ★★ same condition
NOTCH1 p.Gln1466Ter 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/notch1-p-ser2136 (accessed [today's date]).

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