Is SMAD4 p.Pro548= (c.1644A>G) pathogenic?

SMAD4 p.Pro548= (c.1644A>G) is classified Conflicting classifications of pathogenicity in SMAD4 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-01-27). Very rare (popmax 0.005%, amr); Associated with juvenile polyposis syndrome.

What condition is associated with SMAD4 p.Pro548= (c.1644A>G)?

SMAD4 p.Pro548= (c.1644A>G) is associated with juvenile polyposis syndrome, Myhre syndrome, generalized juvenile polyposis/juvenile polyposis coli (ClinVar).

How common is SMAD4 p.Pro548= (c.1644A>G) in the general population?

SMAD4 p.Pro548= (c.1644A>G) is very rare (popmax 0.005%, amr) (gnomAD).

How is Juvenile polyposis syndrome inherited?

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

SMAD4 p.Pro548=

c.1644A>G · rs756795016 · VCV240146

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

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 -0.19	GERP -1.9, phastCons 0.001
Overall
CADD	6.612	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,008 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00112% 18/1,613,770 alleles · very rare exomes 13/1,461,516 · genomes 5/152,254 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0405%	2,467
Admixed Americangrpmax	0.005%	20,003
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)	8.48e-05%	1,179,752

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: SMAD4
Protein: p.Pro548=
Coding: c.1644A>G
MANE Select: NM_005359
dbSNP: rs756795016
Type: single nucleotide variant
Location: chr18:51078452 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.56 · 14 PDB
Residue 548: the mh2 domain

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: Myhre syndrome generalized juvenile polyposis/juvenile polyposis coli juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome 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.Pro548Ala Uncertain significance ★★ ⚠ same residue
SMAD4 p.Pro548Arg Uncertain significance ★ ⚠ same residue
SMAD4 p.Pro548Ser 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-pro548 (accessed [today's date]).

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