Is NOTCH4 p.Ser415Phe (c.1244C>T) pathogenic?

NOTCH4 p.Ser415Phe (c.1244C>T) is classified Uncertain significance in NOTCH4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-29). AlphaMissense: likely benign (0.2052); Ultra-rare (popmax 0.0156%, eas).

How common is NOTCH4 p.Ser415Phe (c.1244C>T) in the general population?

NOTCH4 p.Ser415Phe (c.1244C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about NOTCH4 p.Ser415Phe (c.1244C>T)?

AlphaMissense predicts likely benign (score 0.2052) — an in-silico prediction, not a clinical call.

NOTCH4 p.Ser415Phe

c.1244C>T · rs759797451 · VCV2610496

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2052 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2052	likely benign
REVEL	0.41	indeterminate
SaProt	LLR -9.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5	GERP -3.9, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 28 kb · p 4.5e-14 · regional, not allelic
Overall
CADD	22.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0156% East Asian · 7/44,878 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000434% 7/1,613,960 alleles · ultra-rare exomes 7/1,461,696 · genomes 0/152,264 · joint denominator

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.Ser415Phe
Coding: c.1244C>T
MANE Select: NM_004557
dbSNP: rs759797451
Type: single nucleotide variant
Location: chr6:32220200 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 62.04 · 3 PDB
Residue 415: the egf-like 10 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-ser415phe (accessed [today's date]).

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