Is SMAD2 p.Ser397= (c.1191T>C) pathogenic?

SMAD2 p.Ser397= (c.1191T>C) is classified Likely benign in SMAD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-22). Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with SMAD2 p.Ser397= (c.1191T>C)?

SMAD2 p.Ser397= (c.1191T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SMAD2 p.Ser397= (c.1191T>C) in the general population?

SMAD2 p.Ser397= (c.1191T>C) is absent from gnomAD v4.1 (gnomAD).

SMAD2 p.Ser397=

c.1191T>C · VCV3445800

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 4.2	GERP 1.9, phastCons 1
Overall
CADD	9.791	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SMAD2
Protein: p.Ser397=
Coding: c.1191T>C
MANE Select: NM_005901
Type: single nucleotide variant
Location: chr18:47845429 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.50 · 10 PDB
Residue 397: a UniProt-annotated variant site (in chtd8); the mh2 domain; a UniProt-annotated variant site (in lds6; uncertain significance); an α-helix

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-ser397 (accessed [today's date]).

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