Is SMAD9 p.Pro152= (c.456C>T) pathogenic?

SMAD9 p.Pro152= (c.456C>T) is classified Likely benign in SMAD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). Very rare (popmax 0.00446%, eas); Associated with pulmonary hypertension, primary, 2.

What condition is associated with SMAD9 p.Pro152= (c.456C>T)?

SMAD9 p.Pro152= (c.456C>T) is associated with pulmonary hypertension, primary, 2 (ClinVar).

How common is SMAD9 p.Pro152= (c.456C>T) in the general population?

SMAD9 p.Pro152= (c.456C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

SMAD9 p.Pro152=

c.456C>T · VCV3703241

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Conditions

pulmonary hypertension, primary, 2

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 -1.5	GERP -0.31
Overall
CADD	6.266	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,880 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000186% 3/1,614,152 alleles · very rare exomes 3/1,461,876 · genomes 0/152,276 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,440
Remaining individualsnot grpmax-eligible	0.0016%	62,512

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.Pro152=
Coding: c.456C>T
MANE Select: NM_001127217
Type: single nucleotide variant
Location: chr13:36872872 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.90 · 1 PDB

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.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
SMAD9 p.Arg428His 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-pro152 (accessed [today's date]).

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