Is RAD21 p.Pro283= (c.849C>T) pathogenic?

RAD21 p.Pro283= (c.849C>T) is classified Likely benign in RAD21 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-31). Ultra-rare (popmax 0.0162%, eas); Associated with Cornelia de Lange syndrome 4.

What condition is associated with RAD21 p.Pro283= (c.849C>T)?

RAD21 p.Pro283= (c.849C>T) is associated with Cornelia de Lange syndrome 4 (ClinVar).

How common is RAD21 p.Pro283= (c.849C>T) in the general population?

RAD21 p.Pro283= (c.849C>T) is ultra-rare (popmax 0.0162%, eas) (gnomAD).

RAD21 p.Pro283=

c.849C>T · rs369661655 · VCV1103633

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0162%, eas)

Conditions

Cornelia de Lange syndrome 4

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 -0.39	GERP -5.3, phastCons 0.001
Overall
CADD	11.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0162% East Asian · 7/43,150 alleles

Filtering AF 0.00752% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00531%

Overall 0.0019% 30/1,576,982 alleles · ultra-rare exomes 26/1,429,900 · genomes 4/147,082 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0162%	6,164
Remaining individualsnot grpmax-eligible	0.00985%	10,151
South Asian	0.00231%	43,322
Admixed American	0.00187%	53,390
European (non-Finnish)	0.0012%	83,287

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: RAD21
Protein: p.Pro283=
Coding: c.849C>T
MANE Select: NM_006265
dbSNP: rs369661655
Type: single nucleotide variant
Location: chr8:116856254 (GRCh38)
Gene constraint: LOEUF 0.341 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.49 · 37 PDB
Residue 283: a UniProt-annotated variant site (in cdls4); the 'disordered' region

Full RAD21 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Cornelia de Lange syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RAD21 c.144+1G>A Pathogenic ★★ same condition
RAD21 p.Arg478Ter Pathogenic/Likely pathogenic ★★ same condition
RAD21 p.Arg65Ter Pathogenic/Likely pathogenic ★★ same condition
RAD21 p.Gln436Ter Pathogenic/Likely pathogenic ★★ same condition
RAD21 p.Gly408Ter Pathogenic ★★ same condition
RAD21 p.Ala410Thr Uncertain significance ★★ ⚠ same condition
RAD21 p.Arg404Lys Uncertain significance ★★ ⚠ same condition
RAD21 p.Arg569His 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/rad21-p-pro283 (accessed [today's date]).

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