Is SMC3 p.Arg88= (c.264G>T) pathogenic?

SMC3 p.Arg88= (c.264G>T) is classified Likely benign in SMC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). Ultra-rare (popmax 0.015%, amr); Associated with Cornelia de Lange syndrome 3.

What condition is associated with SMC3 p.Arg88= (c.264G>T)?

SMC3 p.Arg88= (c.264G>T) is associated with Cornelia de Lange syndrome 3 (ClinVar).

How common is SMC3 p.Arg88= (c.264G>T) in the general population?

SMC3 p.Arg88= (c.264G>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

SMC3 p.Arg88=

c.264G>T · rs770562769 · VCV2906842

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Conditions

Cornelia de Lange syndrome 3

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 -0.034	GERP -0.99, phastCons 0.2
Overall
CADD	7.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.015% Admixed American · 9/59,998 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.000618% 9/1,455,562 alleles · ultra-rare

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: SMC3
Protein: p.Arg88=
Coding: c.264G>T
MANE Select: NM_005445
dbSNP: rs770562769
Type: single nucleotide variant
Location: chr10:110577486 (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.Arg88Gln Uncertain significance ★ ⚠ same residue
SMC3 p.Arg88Trp 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

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-arg88 (accessed [today's date]).

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