Is SMC3 p.Arg236Pro (c.707G>C) pathogenic?

SMC3 p.Arg236Pro (c.707G>C) is classified Likely pathogenic in SMC3 (ClinVar, Single submitter, 3 submitters; last evaluated 2014-02-24). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with Cornelia de Lange syndrome 3.

What condition is associated with SMC3 p.Arg236Pro (c.707G>C)?

SMC3 p.Arg236Pro (c.707G>C) is associated with Cornelia de Lange syndrome 3 (ClinVar).

How common is SMC3 p.Arg236Pro (c.707G>C) in the general population?

SMC3 p.Arg236Pro (c.707G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SMC3 p.Arg236Pro (c.707G>C)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

SMC3 p.Arg236Pro

c.707G>C · rs587784429 · VCV159990

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cornelia de Lange syndrome 3

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic ✓ concordant with ClinVar · top 4% in SMC3
REVEL	0.937	strongly pathogenic-leaning
SaProt	LLR -8.60	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.33	constrained · MANE · 16 kb · p 3.2e-44 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

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: SMC3
Protein: p.Arg236Pro
Coding: c.707G>C
MANE Select: NM_005445
dbSNP: rs587784429
Type: single nucleotide variant
Location: chr10:110582082 (GRCh38)
Gene constraint: LOEUF 0.132 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 82.37 · 12 PDB

Full SMC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cornelia de Lange syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMC3 p.Arg236His Uncertain significance ★ ⚠ same residue
SMC3 p.Gln1147Glu Pathogenic ★★ same condition
SMC3 p.Glu95Lys Likely pathogenic ★★ same condition
SMC3 p.Ile196Thr Pathogenic/Likely pathogenic ★★ same condition
SMC3 p.Met648Val Pathogenic/Likely pathogenic ★★ same condition
SMC3 p.Trp473Gly Likely pathogenic ★★ same condition
SMC3 c.430-3T>C Uncertain significance ★★ same condition
SMC3 p.Ala484Gly 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/smc3-p-arg236pro (accessed [today's date]).

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