Is SMAD2 p.Pro435Arg (c.1304C>G) pathogenic?

SMAD2 p.Pro435Arg (c.1304C>G) is classified Uncertain significance in SMAD2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-06). AlphaMissense: likely pathogenic (0.9998); Absent from gnomAD v4.1; Associated with SMAD2-related disorder.

What condition is associated with SMAD2 p.Pro435Arg (c.1304C>G)?

SMAD2 p.Pro435Arg (c.1304C>G) is associated with SMAD2-related disorder (ClinVar).

How common is SMAD2 p.Pro435Arg (c.1304C>G) in the general population?

SMAD2 p.Pro435Arg (c.1304C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMAD2 p.Pro435Arg (c.1304C>G)?

AlphaMissense predicts likely pathogenic (score 0.9998) — an in-silico prediction, not a clinical call.

SMAD2 p.Pro435Arg

c.1304C>G · rs2144276937 · VCV3031308

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9998 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SMAD2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9998	likely pathogenic
REVEL	0.981	strongly pathogenic-leaning
SaProt	LLR -16.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 3,590 bp · p 5.2e-12 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Pro435Arg
Coding: c.1304C>G
MANE Select: NM_005901
dbSNP: rs2144276937
Type: single nucleotide variant
Location: chr18:47841927 (GRCh38)
Gene constraint: LOEUF 0.249 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 78.50 · 10 PDB
Residue 435: a UniProt-annotated variant site (in chtd8); the mh2 domain; a β-strand

Full SMAD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SMAD2-related disorder

Similar variants

SMAD2 p.Pro435Ser Uncertain significance ★★ ⚠ same residue
SMAD2 p.Gln264Ter Pathogenic/Likely pathogenic ★★ same condition
SMAD2 c.997+1G>T Pathogenic ★ same condition
SMAD2 p.Arg133His Uncertain significance ★ ⚠ same condition
SMAD2 p.Gly122Arg Uncertain significance ★ ⚠ same condition
SMAD2 p.His140Tyr Uncertain significance ⚠ same condition
SMAD2 p.Ser306Leu Uncertain significance ⚠ same condition
SMAD2 c.237-2A>G Likely pathogenic ★★ same type

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-pro435arg (accessed [today's date]).

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