Is NOTCH4 p.Pro800= (c.2400G>A) pathogenic?

NOTCH4 p.Pro800= (c.2400G>A) is classified Likely benign in NOTCH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-01). Rare (popmax 0.532%, amr).

How common is NOTCH4 p.Pro800= (c.2400G>A) in the general population?

NOTCH4 p.Pro800= (c.2400G>A) is rare (popmax 0.532%, amr) (gnomAD).

NOTCH4 p.Pro800=

c.2400G>A · VCV3257660

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.532%, amr)

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 -2.8	GERP -3.3
Overall
CADD	1.597	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.532% Admixed American · 319/59,992 alleles

Filtering AF 0.484% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.465%

Overall 0.131% 2,116/1,613,932 alleles · rare exomes 1,866/1,461,736 · genomes 250/152,196 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	2.77%	36
Admixed Americangrpmax	0.532%	188
Remaining individualsnot grpmax-eligible	0.267%	374
Middle Eastern	0.231%	432
European (non-Finnish)	0.065%	1,538
African / African-American	0.024%	4,167
Finnishnot grpmax-eligible	0.0172%	5,821
East Asian	0.00223%	44,870

Ashkenazi Jewish 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: NOTCH4
Protein: p.Pro800=
Coding: c.2400G>A
MANE Select: NM_004557
Type: single nucleotide variant
Location: chr6:32213173 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.04 · 3 PDB
Residue 800: the egf-like 20 domain

Full NOTCH4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NOTCH4 p.Ala526= Benign ★★ same type
NOTCH4 p.Cys815Gly Benign/Likely benign ★★ same type
NOTCH4 p.Gln1469= Benign/Likely benign ★★ same type
NOTCH4 p.Leu1610= Benign ★★ same type
NOTCH4 p.Val600Leu Likely benign ★★ same type
NOTCH4 c.5299-1G>A Uncertain significance ★ same type
NOTCH4 c.5299-1G>T Uncertain significance ★ same type
NOTCH4 p.Ala1022Thr Uncertain significance ★ ⚠ 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/notch4-p-pro800 (accessed [today's date]).

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