Is DCDC2 p.Glu281del (c.840AGA[1]) pathogenic?

DCDC2 p.Glu281del (c.840AGA[1]) is classified Uncertain significance in DCDC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-09-30). Ultra-rare (popmax 0.0231%, sas); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Glu281del (c.840AGA[1])?

DCDC2 p.Glu281del (c.840AGA[1]) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66, nephronophthisis 19 (ClinVar).

How common is DCDC2 p.Glu281del (c.840AGA[1]) in the general population?

DCDC2 p.Glu281del (c.840AGA[1]) is ultra-rare (popmax 0.0231%, sas) (gnomAD).

How is Isolated neonatal sclerosing cholangitis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

DCDC2 p.Glu281del

c.840AGA[1] · rs760375899 · VCV1338443

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0231%, sas)

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.7	GERP -3.4
Overall
CADD	8.103	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0231% South Asian · 21/91,010 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0031% 50/1,613,372 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0231%	4,334
East Asian	0.0223%	4,485
Remaining individualsnot grpmax-eligible	0.016%	6,246
African / African-American	0.008%	12,493
European (non-Finnish)	0.000254%	393,196

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: DCDC2
Protein: p.Glu281del
Coding: c.840AGA[1]
MANE Select: NM_016356
dbSNP: rs760375899
Type: Microsatellite
Location: chr6:24278126 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 281: a UniProt-annotated variant site (in nsc); the 'disordered' region

Full DCDC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

isolated neonatal sclerosing cholangitis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 66 nephronophthisis 19

For Isolated neonatal sclerosing cholangitis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

DCDC2 p.Ser42fs Pathogenic ★★ same condition
DCDC2 c.294-21GTTT[2] Benign/Likely benign ★★ same condition
DCDC2 p.Lys40del Uncertain significance ★ same condition
DCDC2 c.294-2A>G Pathogenic ★★ same condition
DCDC2 c.349-2A>G Pathogenic ★★ same condition
DCDC2 c.705-2A>G Pathogenic ★★ same condition
DCDC2 p.Ala324fs Pathogenic/Likely pathogenic ★★ same condition
DCDC2 p.Gly315fs Pathogenic/Likely 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/dcdc2-p-glu281del (accessed [today's date]).

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