Is SMAD2 p.Pro9= (c.27G>A) pathogenic?

SMAD2 p.Pro9= (c.27G>A) is classified Benign/Likely benign in SMAD2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-27). Rare (popmax 0.206%, sas); Associated with Inborn genetic diseases.

What condition is associated with SMAD2 p.Pro9= (c.27G>A)?

SMAD2 p.Pro9= (c.27G>A) is associated with Inborn genetic diseases (ClinVar).

How common is SMAD2 p.Pro9= (c.27G>A) in the general population?

SMAD2 p.Pro9= (c.27G>A) is rare (popmax 0.206%, sas) (gnomAD).

SMAD2 p.Pro9=

c.27G>A · rs546743584 · VCV1196017

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.206%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.49	GERP -5.7, phastCons 0.09
Overall
CADD	11.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.206% South Asian · 188/91,074 alleles

Filtering AF 0.182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.173%

Overall 0.0123% 198/1,613,976 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.206%	484
Middle Eastern	0.033%	3,031
Remaining individualsnot grpmax-eligible	0.008%	12,500
East Asian	0.00446%	22,443
European (non-Finnish)	8.47e-05%	1,179,956

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: SMAD2
Protein: p.Pro9=
Coding: c.27G>A
MANE Select: NM_005901
dbSNP: rs546743584
Type: single nucleotide variant
Location: chr18:47896730 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.50 · 10 PDB

Full SMAD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMAD2 p.Pro9Leu Uncertain significance ★★ ⚠ same residue
SMAD2 p.Pro9Gln Uncertain significance ★ ⚠ same residue
SMAD2 p.Ala395Ser Uncertain significance ★★ ⚠ same condition
SMAD2 p.Asn307Asp Uncertain significance ★★ ⚠ same condition
SMAD2 p.Asn318Ser Uncertain significance ★★ ⚠ same condition
SMAD2 p.Asn361Ser Uncertain significance ★★ ⚠ same condition
SMAD2 p.Asn91Asp Uncertain significance ★★ ⚠ same condition
SMAD2 p.Cys81Phe Uncertain significance ★★ ⚠ 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/smad2-p-pro9 (accessed [today's date]).

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