Is DCDC2 p.Pro385Leu (c.1154C>T) pathogenic?

DCDC2 p.Pro385Leu (c.1154C>T) is classified Uncertain significance in DCDC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-25). AlphaMissense: likely benign (0.0727); Very rare (popmax 0.00508%, nfe); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Pro385Leu (c.1154C>T)?

DCDC2 p.Pro385Leu (c.1154C>T) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66 (ClinVar).

How common is DCDC2 p.Pro385Leu (c.1154C>T) in the general population?

DCDC2 p.Pro385Leu (c.1154C>T) is very rare (popmax 0.00508%, nfe) (gnomAD).

How is Isolated neonatal sclerosing cholangitis inherited?

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

What do computational predictors say about DCDC2 p.Pro385Leu (c.1154C>T)?

AlphaMissense predicts likely benign (score 0.0727) — an in-silico prediction, not a clinical call.

DCDC2 p.Pro385Leu

c.1154C>T · rs773020868 · VCV660101

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0727 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00508%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
AlphaMissense	0.0727	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -6.39	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.6, phastCons 0.79
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	14.93	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00508% European (non-Finnish) · 60/1,180,046 alleles

Filtering AF 0.00402% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00362%

Overall 0.00384% 62/1,614,030 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00508%	19,667
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,910

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.Pro385Leu
Coding: c.1154C>T
MANE Select: NM_016356
dbSNP: rs773020868
Type: single nucleotide variant
Location: chr6:24178502 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 385: 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

For Isolated neonatal sclerosing cholangitis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

DCDC2 p.Pro385Arg Uncertain significance ★ ⚠ same residue
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.Leu297Ter Pathogenic ★★ same condition
DCDC2 p.Met1Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
DCDC2 p.Ser128Ter Pathogenic/Likely pathogenic ★★ same condition
DCDC2 p.Ala384Gly 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/dcdc2-p-pro385leu (accessed [today's date]).

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