Is DCDC2 p.Lys298fs (c.892_896del) pathogenic?

DCDC2 p.Lys298fs (c.892896del) is classified Likely pathogenic in DCDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-08-19). Very rare (popmax 0.00267%, afr); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Lys298fs (c.892_896del)?

DCDC2 p.Lys298fs (c.892_896del) is associated with isolated neonatal sclerosing cholangitis (ClinVar).

How common is DCDC2 p.Lys298fs (c.892_896del) in the general population?

DCDC2 p.Lys298fs (c.892_896del) is very rare (popmax 0.00267%, afr) (gnomAD).

How is Isolated neonatal sclerosing cholangitis inherited?

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

DCDC2 p.Lys298fs

c.892_896del · VCV4886940

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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 7 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.3	GERP -2.7
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,834 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,248 alleles · very 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: DCDC2
Protein: p.Lys298fs
Coding: c.892_896del
MANE Select: NM_016356
Type: Deletion
Location: chr6:24278075 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 298: 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

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.Glu222fs Likely pathogenic ★ same condition
DCDC2 p.Leu179fs Pathogenic ★ same condition
DCDC2 p.Leu97fs 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-lys298fs (accessed [today's date]).

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