Is SMAD9 p.Pro99= (c.297G>A) pathogenic?

SMAD9 p.Pro99= (c.297G>A) is classified Likely benign in SMAD9 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-30). Ultra-rare (popmax 0.0351%, sas); Associated with pulmonary hypertension, primary, 2.

What condition is associated with SMAD9 p.Pro99= (c.297G>A)?

SMAD9 p.Pro99= (c.297G>A) is associated with pulmonary hypertension, primary, 2 (ClinVar).

How common is SMAD9 p.Pro99= (c.297G>A) in the general population?

SMAD9 p.Pro99= (c.297G>A) is ultra-rare (popmax 0.0351%, sas) (gnomAD).

SMAD9 p.Pro99=

c.297G>A · VCV3704676

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, sas)

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 -16	GERP -12
Overall
CADD	0.623	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0351% South Asian · 32/91,088 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00266% 43/1,614,062 alleles · ultra-rare exomes 43/1,461,720 · genomes 0/152,342 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0351%	2,846
Middle Eastern	0.0165%	6,060
Admixed American	0.00333%	30,014
East Asian	0.00223%	44,876
Remaining individualsnot grpmax-eligible	0.0016%	62,508
African / African-American	0.00133%	75,060
European (non-Finnish)	0.000424%	236,007

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.Pro99=
Coding: c.297G>A
MANE Select: NM_001127217
Type: single nucleotide variant
Location: chr13:36879393 (GRCh38)
Gene constraint: LOEUF 1.018 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.90 · 1 PDB
Residue 99: the mh1 domain

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.Pro99Leu 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-pro99 (accessed [today's date]).

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