Is NOTCH1 p.Pro62= (c.186G>C) pathogenic?

NOTCH1 p.Pro62= (c.186G>C) is classified Benign/Likely benign in NOTCH1 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-06-01). Rare (popmax 0.604%, mid); Associated with Adams-Oliver syndrome 5.

What condition is associated with NOTCH1 p.Pro62= (c.186G>C)?

NOTCH1 p.Pro62= (c.186G>C) is associated with Adams-Oliver syndrome 5, connective tissue disorder, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Pro62= (c.186G>C) in the general population?

NOTCH1 p.Pro62= (c.186G>C) is rare (popmax 0.604%, mid) (gnomAD).

NOTCH1 p.Pro62=

c.186G>C · rs374320445 · VCV415434

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

rare (popmax 0.604%, mid)

Conditions

Adams-Oliver syndrome 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.37	GERP -2.7, phastCons 0.018
Overall
CADD	6.081	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.604% Middle Eastern · 36/5,956 alleles

Filtering AF 0.449% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.395%

Overall 0.0381% 604/1,587,204 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.604%	165
Admixed American	0.0841%	1,189
South Asian	0.0831%	1,204
Remaining individualsnot grpmax-eligible	0.0813%	1,229
Ashkenazi Jewishnot grpmax-eligible	0.0655%	1,528
European (non-Finnish)	0.031%	3,224
African / African-American	0.0228%	4,391

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.Pro62=
Coding: c.186G>C
MANE Select: NM_017617
dbSNP: rs374320445
Type: single nucleotide variant
Location: chr9:136523934 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 62: the egf-like 2 domain

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: connective tissue disorder 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-pro62 (accessed [today's date]).

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