Is SMAD9 p.Pro201= (c.603G>T) pathogenic?

SMAD9 p.Pro201= (c.603G>T) is classified Likely benign in SMAD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-18). Very rare (popmax 0.00136%, nfe); Associated with pulmonary hypertension, primary, 2.

What condition is associated with SMAD9 p.Pro201= (c.603G>T)?

SMAD9 p.Pro201= (c.603G>T) is associated with pulmonary hypertension, primary, 2 (ClinVar).

How common is SMAD9 p.Pro201= (c.603G>T) in the general population?

SMAD9 p.Pro201= (c.603G>T) is very rare (popmax 0.00136%, nfe) (gnomAD).

SMAD9 p.Pro201=

c.603G>T · rs934648707 · VCV474935

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Conditions

pulmonary hypertension, primary, 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.5	GERP -11
Overall
CADD	1.724	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,972 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.000991% 16/1,613,882 alleles · very rare exomes 16/1,461,862 · genomes 0/152,020 · joint denominator

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: SMAD9
Protein: p.Pro201=
Coding: c.603G>T
MANE Select: NM_001127217
dbSNP: rs934648707
Type: single nucleotide variant
Location: chr13:36872725 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.90 · 1 PDB
Residue 201: the 'disordered' region

Full SMAD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

pulmonary hypertension, primary, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMAD9 p.Pro201Leu Uncertain significance ★★ ⚠ same residue
SMAD9 p.Arg294Ter Pathogenic ★★ same condition
SMAD9 p.Gln271Ter Pathogenic/Likely pathogenic ★★ same condition
SMAD9 p.Ala277Val Uncertain significance ★★ ⚠ same condition
SMAD9 p.Ala424Thr Uncertain significance ★★ ⚠ same condition
SMAD9 p.Ala58Ser Uncertain significance ★★ ⚠ same condition
SMAD9 p.Arg161His Uncertain significance ★★ ⚠ same condition
SMAD9 p.Arg415Trp 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/smad9-p-pro201 (accessed [today's date]).

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