Is SMAD4 p.Pro550= (c.1650T>C) pathogenic?

SMAD4 p.Pro550= (c.1650T>C) is classified Benign/Likely benign in SMAD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-24). Absent from gnomAD v4.1; Associated with juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome.

How common is SMAD4 p.Pro550= (c.1650T>C) in the general population?

SMAD4 p.Pro550= (c.1650T>C) is absent from gnomAD v4.1 (gnomAD).

SMAD4 p.Pro550=

Q: What condition is associated with SMAD4 p.Pro550= (c.1650T>C)?

SMAD4 p.Pro550= (c.1650T>C) is associated with juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, juvenile polyposis syndrome (ClinVar).

c.1650T>C · rs1910528129 · VCV2134735

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

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 -0.27	GERP -3.7, phastCons 0.42
Overall
CADD	6.601	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMAD4
Protein: p.Pro550=
Coding: c.1650T>C
MANE Select: NM_005359
dbSNP: rs1910528129
Type: single nucleotide variant
Location: chr18:51078458 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 14 PDB
Residue 550: the mh2 domain

Full SMAD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: juvenile polyposis syndrome

Similar variants

SMAD4 p.Pro550Leu Uncertain significance ★★ ⚠ same residue
SMAD4 p.Pro550Ser Uncertain significance ★★ ⚠ same residue
SMAD4 c.1140-1G>A Pathogenic ★★ same condition
SMAD4 c.1308+1G>A Pathogenic/Likely pathogenic ★★ same condition
SMAD4 c.1308+2T>G Likely pathogenic ★★ same condition
SMAD4 c.1309-1G>A Pathogenic/Likely pathogenic ★★ same condition
SMAD4 c.1447+2T>C Pathogenic ★★ same condition
SMAD4 c.249+1G>T 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/smad4-p-pro550 (accessed [today's date]).

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