Is SMAD2 p.Pro164= (c.492T>C) pathogenic?

SMAD2 p.Pro164= (c.492T>C) is classified Likely benign in SMAD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-23). Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with SMAD2 p.Pro164= (c.492T>C)?

SMAD2 p.Pro164= (c.492T>C) is associated with Inborn genetic diseases (ClinVar).

How common is SMAD2 p.Pro164= (c.492T>C) in the general population?

SMAD2 p.Pro164= (c.492T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

SMAD2 p.Pro164=

c.492T>C · rs554216321 · VCV1744202

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

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 2.1	GERP -3.5, phastCons 1
Overall
CADD	10.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,900 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000434% 7/1,613,610 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,900
European (non-Finnish)	0.000509%	196,623

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.Pro164=
Coding: c.492T>C
MANE Select: NM_005901
dbSNP: rs554216321
Type: single nucleotide variant
Location: chr18:47869271 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.50 · 10 PDB
Residue 164: the mh1 domain; 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-pro164 (accessed [today's date]).

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