Is NOTCH1 p.Ala683= (c.2049G>A) pathogenic?

NOTCH1 p.Ala683= (c.2049G>A) is classified Benign/Likely benign in NOTCH1 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-02-04). Rare (popmax 0.132%, nfe); Associated with connective tissue disorder.

What condition is associated with NOTCH1 p.Ala683= (c.2049G>A)?

NOTCH1 p.Ala683= (c.2049G>A) is associated with connective tissue disorder, Adams-Oliver syndrome 5, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is NOTCH1 p.Ala683= (c.2049G>A) in the general population?

NOTCH1 p.Ala683= (c.2049G>A) is rare (popmax 0.132%, nfe) (gnomAD).

NOTCH1 p.Ala683=

c.2049G>A · rs61751553 · VCV241121

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

rare (popmax 0.132%, nfe)

Conditions

connective tissue disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.40	acceptor gain · deltas
Constraint at this position
Conservation	phyloP -16	GERP -4.5
Overall
CADD	12.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.132% European (non-Finnish) · 1,563/1,179,812 alleles

Filtering AF 0.127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.125%

Overall 0.112% 1,805/1,612,312 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.203%	494
European (non-Finnish)grpmax	0.132%	755
Remaining individualsnot grpmax-eligible	0.0865%	1,156
Admixed American	0.055%	1,817
African / African-American	0.028%	3,572
South Asian	0.00659%	15,168
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,592

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala683=
Coding: c.2049G>A
MANE Select: NM_017617
dbSNP: rs61751553
Type: single nucleotide variant
Location: chr9:136514668 (GRCh38)
Gene constraint: LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.74 · 29 PDB
Residue 683: a disulfide bond; the egf-like 18; calcium-binding domain

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

Disease context

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Adams-Oliver syndrome 5 familial thoracic aortic aneurysm and aortic dissection aortic valve disease 1

Similar variants

NOTCH1 p.Ala683Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
NOTCH1 p.Ala683Val Likely benign ★ same residue
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

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-ala683 (accessed [today's date]).

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