Is SMAD2 p.Pro201= (c.603A>T) pathogenic?

SMAD2 p.Pro201= (c.603A>T) is classified Likely benign in SMAD2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-10). Ultra-rare (popmax 0.0379%, eas); Associated with Inborn genetic diseases.

What condition is associated with SMAD2 p.Pro201= (c.603A>T)?

SMAD2 p.Pro201= (c.603A>T) is associated with Inborn genetic diseases (ClinVar).

How common is SMAD2 p.Pro201= (c.603A>T) in the general population?

SMAD2 p.Pro201= (c.603A>T) is ultra-rare (popmax 0.0379%, eas) (gnomAD).

SMAD2 p.Pro201=

c.603A>T · rs769301053 · VCV1751214

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0379%, eas)

Conditions

Inborn genetic diseases

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 0.44	GERP 1.1, phastCons 1
Overall
CADD	11.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0379% East Asian · 17/44,848 alleles

Filtering AF 0.0241% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0198%

Overall 0.00118% 19/1,611,780 alleles · ultra-rare exomes 17/1,459,802 · genomes 2/151,978 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0379%	2,638
Remaining individualsnot grpmax-eligible	0.0032%	31,216

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.Pro201=
Coding: c.603A>T
MANE Select: NM_005901
dbSNP: rs769301053
Type: single nucleotide variant
Location: chr18:47868375 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.50 · 10 PDB
Residue 201: a UniProt-annotated variant site (in chtd8)

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.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
SMAD2 p.Gln236His Uncertain significance ★★ ⚠ same condition
SMAD2 p.Ile127Met 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-pro201 (accessed [today's date]).

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