Is DCDC2 p.Ile177fs (c.529dup) pathogenic?

DCDC2 p.Ile177fs (c.529dup) is classified Pathogenic in DCDC2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-08-19). Very rare (popmax 0.00144%, nfe); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Ile177fs (c.529dup)?

DCDC2 p.Ile177fs (c.529dup) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66, nephronophthisis 19 (ClinVar).

How common is DCDC2 p.Ile177fs (c.529dup) in the general population?

DCDC2 p.Ile177fs (c.529dup) is very rare (popmax 0.00144%, nfe) (gnomAD).

How is Isolated neonatal sclerosing cholangitis inherited?

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

DCDC2 p.Ile177fs

c.529dup · rs904944428 · VCV417769

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

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 4 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Overall
CADD	33.0	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 0.00144% European (non-Finnish) · 17/1,180,034 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00124% 20/1,613,970 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)grpmax	0.00144%	69,414
African / African-American	0.00134%	74,898

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile177fs
Coding: c.529dup
MANE Select: NM_016356
dbSNP: rs904944428
Type: Duplication
Location: chr6:24301742 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 177: the doublecortin 2 domain

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.Ala324fs Pathogenic/Likely pathogenic ★★ same condition
DCDC2 c.349-16dup Benign/Likely benign ★★ same condition
DCDC2 p.Val184fs Likely pathogenic ★ same condition
DCDC2 c.760-16dup 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.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-ile177fs (accessed [today's date]).

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