Is DCDC2 p.Glu222fs (c.665del) pathogenic?

DCDC2 p.Glu222fs (c.665del) is classified Likely pathogenic in DCDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-08-19). Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Glu222fs (c.665del)?

DCDC2 p.Glu222fs (c.665del) is associated with isolated neonatal sclerosing cholangitis (ClinVar).

How is Isolated neonatal sclerosing cholangitis inherited?

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

DCDC2 p.Glu222fs

c.665del · VCV4886939

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 5 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.15	GERP -2, phastCons 0.67

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: DCDC2
Protein: p.Glu222fs
Coding: c.665del
MANE Select: NM_016356
Type: Deletion
Location: chr6:24290971 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 222: a UniProt-annotated variant site (in nsc); an α-helix

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

For Isolated neonatal sclerosing cholangitis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

DCDC2 p.Gly315fs Pathogenic/Likely pathogenic ★★ same condition
DCDC2 c.923-283_1023+141del Likely pathogenic ★ same condition
DCDC2 p.Leu179fs Pathogenic ★ same condition
DCDC2 p.Leu97fs Likely pathogenic ★ same condition
DCDC2 p.Lys298fs Likely pathogenic ★ same condition
DCDC2 c.705-11del Likely benign ★ same condition
DCDC2 c.923-12_923-9del Likely benign ★ same condition
DCDC2 c.426_557del 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-glu222fs (accessed [today's date]).

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