Is DCDC2 p.Leu149Phe (c.445C>T) pathogenic?

DCDC2 p.Leu149Phe (c.445C>T) is classified Uncertain significance in DCDC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-07-02). AlphaMissense: likely benign (0.2); Ultra-rare (popmax 0.028%, afr); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Leu149Phe (c.445C>T)?

DCDC2 p.Leu149Phe (c.445C>T) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66, nephronophthisis 19 (ClinVar).

How common is DCDC2 p.Leu149Phe (c.445C>T) in the general population?

DCDC2 p.Leu149Phe (c.445C>T) is ultra-rare (popmax 0.028%, afr) (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.Leu149Phe (c.445C>T)?

AlphaMissense predicts likely benign (score 0.2) — an in-silico prediction, not a clinical call.

DCDC2 p.Leu149Phe

c.445C>T · rs200595563 · VCV502792

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
AlphaMissense	0.2	likely benign
REVEL	0.466	indeterminate
SaProt	LLR -11.86	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.028% African / African-American · 21/75,000 alleles

Filtering AF 0.0187% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.00149% 24/1,614,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.028%	3,571
Admixed American	0.00167%	60,018
Remaining individualsnot grpmax-eligible	0.0016%	62,510
European (non-Finnish)	8.47e-05%	1,180,034

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.Leu149Phe
Coding: c.445C>T
MANE Select: NM_016356
dbSNP: rs200595563
Type: single nucleotide variant
Location: chr6:24301827 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 149: the doublecortin 2 domain; a β-strand

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.Leu149= Likely benign ★ 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-leu149phe (accessed [today's date]).

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