Is SMC1A p.Ser445= (c.1335C>T) pathogenic?

SMC1A p.Ser445= (c.1335C>T) is classified Pathogenic/Likely pathogenic in SMC1A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-18). Absent from gnomAD v4.1; Associated with Cornelia de Lange syndrome 2.

What condition is associated with SMC1A p.Ser445= (c.1335C>T)?

SMC1A p.Ser445= (c.1335C>T) is associated with Cornelia de Lange syndrome 2 (ClinVar).

How common is SMC1A p.Ser445= (c.1335C>T) in the general population?

SMC1A p.Ser445= (c.1335C>T) is absent from gnomAD v4.1 (gnomAD).

SMC1A p.Ser445=

c.1335C>T · rs2520944818 · VCV2033254

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Cornelia de Lange syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.99	donor gain · deltas
Pangolin	Δ0.88	gain · loss 0.87 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Overall
CADD	27.4	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: SMC1A
Protein: p.Ser445=
Coding: c.1335C>T
MANE Select: NM_006306
dbSNP: rs2520944818
Type: single nucleotide variant
Location: chrX:53409423 (GRCh38)
Structure: AlphaFold pLDDT 83.02 · 18 PDB
Residue 445: a UniProt-annotated variant site (in dee85)

Full SMC1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cornelia de Lange syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SMC1A c.1114-2A>G Pathogenic ★★ same condition
SMC1A c.1546-2A>C Likely pathogenic ★★ same condition
SMC1A p.Arg1035Ter Pathogenic/Likely pathogenic ★★ same condition
SMC1A p.Arg1049Gln Pathogenic/Likely pathogenic ★★ ⚠ same condition
SMC1A p.Arg1049Ter Pathogenic ★★ same condition
SMC1A p.Arg1066Cys Pathogenic/Likely pathogenic ★★ same condition
SMC1A p.Arg1066His Pathogenic/Likely pathogenic ★★ same condition
SMC1A p.Arg171Ter Pathogenic ★★ 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/smc1a-p-ser445 (accessed [today's date]).

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