NM_000435.3:c.1729A>C

Variant names:

• chr19-15187216-T-G
• rs368181126
• NM_000435.3:c.1729A>C
• NOTCH3 p.Thr577Pro

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

+3 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 3 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_ModerateO7_ModerateB3_Supporting

The NM_000435.3(NOTCH3):c.1729A>C (p.Thr577Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene NOTCH3 is a tumor suppressor gene (CancerMine: 5 TSG, 18 oncogene, 13 driver citations). The gene NOTCH3 is a known oncogene (CancerMine: 5 TSG, 18 oncogene, 13 driver citations). The gene NOTCH3 is a cancer driver gene (CancerMine: 5 TSG, 18 oncogene, 13 driver citations). The variant allele was found at a cumulative frequency of 0.000000684 (AC=1) in the gnomAD database across 1,461,766 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000116. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T577A: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 447797)

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOTCH3 NM_000435.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.398
• Publications: 4 publications found

Genes affected

NOTCH3 (HGNC:7883): (notch receptor 3) This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

NOTCH3 Gene-Disease associations (from GenCC):

• cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Orphanet, Ambry Genetics
• lateral meningocele syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
• infantile myofibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myofibromatosis, infantile, 2

  Inheritance: AD Classification: LIMITED Submitted by: G2P
• inherited thrombocytopenia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen
• pulmonary arterial hypertension

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 3 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = 0.000012, AC = 1 — absent/extremely rare (O3 moderate [+2])
	O7Mutational hotspot or critical domain		Moderate: ≥10 same AA change, or strong functional domain signal; No cancerhotspots.org hit at this position; UniProt domain: 11 pathogenic, 5 benign (OR vs. background: 10.5).; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0); Variant does not impact splicing — splice-hotspot path not applicable
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000435.3. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NOTCH3 NM_000435.3	MANE Select	c.1729A>C p.Thr577Pro	missense	Exon 11 of 33	Prot: NP_000426.2 UniProt:

NOTCH3 NM_000435.3

MANE Select

HGVSc / HGVSpc.1729A>Cp.Thr577Pro

Exon rankExon 11 of 33

missense

Prot: NP_000426.2UniProt: Q9UM47

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	NOTCH3 ENST00000263388.7	TSL:1MANE Select	c.1729A>C p.Thr577Pro	missense	Exon 11 of 33	Prot: ENSP00000263388.1 UniProt:
	NOTCH3 ENST00000931534.1		c.1729A>C p.Thr577Pro	missense	Exon 11 of 34	Prot: ENSP00000601593.1 UniProt:
	NOTCH3 ENST00000931532.1		c.1708A>C p.Thr570Pro	missense	Exon 11 of 32	Prot: ENSP00000601591.1 UniProt:

NOTCH3 ENST00000263388.7

TSL:1MANE Select

HGVSc / HGVSpc.1729A>Cp.Thr577Pro

Exon rankExon 11 of 33

missense

Prot: ENSP00000263388.1UniProt: Q9UM47

NOTCH3 ENST00000931534.1

HGVSc / HGVSpc.1729A>Cp.Thr577Pro

Exon rankExon 11 of 34

missense

Prot: ENSP00000601593.1UniProt: A0ACI8TLY8

NOTCH3 ENST00000931532.1

HGVSc / HGVSpc.1708A>Cp.Thr570Pro

Exon rankExon 11 of 32

missense

Prot: ENSP00000601591.1UniProt: A0ACI8TLB6

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 3 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD4 exome	AF: 6.84e-7	AC:1	Hom:0	AN:1461766	Cov:33
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 3 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	12
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	0.0099	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.25
FATHMM_MKL	Benign	0.52	D
FuncVEP CTI	Benign	0.11
GPN-Star LLR	N/A	-8.3
GPN-Star score	N/A	8.3
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.65	T
Mutation Taster	N/A	38/62	disease causing
MutationAssessor	Benign	0.56	N
PhyloP100	Benign	0.40
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Benign	0.21	T
Sift4G	Benign	0.27	T
Varity_R	N/A	0.38
VESM-3B	Benign	-3.3

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs368181126;

hg19: chr19-15298027;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar