Is SMAD4 p.Arg445= (c.1335A>G) pathogenic?

SMAD4 p.Arg445= (c.1335A>G) is classified Likely benign in SMAD4 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-20). Absent from gnomAD v4.1; Associated with juvenile polyposis syndrome.

What condition is associated with SMAD4 p.Arg445= (c.1335A>G)?

SMAD4 p.Arg445= (c.1335A>G) is associated with juvenile polyposis syndrome, hereditary neoplastic syndrome, familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is SMAD4 p.Arg445= (c.1335A>G) in the general population?

SMAD4 p.Arg445= (c.1335A>G) is absent from gnomAD v4.1 (gnomAD).

How is Juvenile polyposis syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

SMAD4 p.Arg445=

c.1335A>G · rs2144473656 · VCV1770222

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

juvenile polyposis 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 -2.1	GERP -4
Overall
CADD	1.391	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.Arg445=
Coding: c.1335A>G
MANE Select: NM_005359
dbSNP: rs2144473656
Type: single nucleotide variant
Location: chr18:51076664 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 14 PDB
Residue 445: the mh2 domain; an α-helix

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

Disease context

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

Also linked: hereditary neoplastic syndrome familial thoracic aortic aneurysm and aortic dissection

For Juvenile polyposis syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

SMAD4 p.Arg445Ter Pathogenic ★★ same residue
SMAD4 p.Arg445Gly Uncertain significance ★★ ⚠ same residue
SMAD4 p.Arg445Gln 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

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-arg445 (accessed [today's date]).

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