Is DCDC2 p.Arg155Cys (c.463C>T) pathogenic?

DCDC2 p.Arg155Cys (c.463C>T) is classified Uncertain significance in DCDC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-27). AlphaMissense: likely pathogenic (0.6949); Very rare (popmax 0.00878%, sas); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Arg155Cys (c.463C>T)?

DCDC2 p.Arg155Cys (c.463C>T) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66 (ClinVar).

How common is DCDC2 p.Arg155Cys (c.463C>T) in the general population?

DCDC2 p.Arg155Cys (c.463C>T) is very rare (popmax 0.00878%, sas) (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.Arg155Cys (c.463C>T)?

AlphaMissense predicts likely pathogenic (score 0.6949) — an in-silico prediction, not a clinical call.

DCDC2 p.Arg155Cys

c.463C>T · rs368811969 · VCV2186477

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
AlphaMissense	0.6949	likely pathogenic
REVEL	0.876	moderately pathogenic-leaning
SaProt	LLR -16.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.35 · evaluated, not missing
Pangolin	Δ0.23	loss · gain 0.14 · SpliceAI below 0.2 · independent
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00878% South Asian · 8/91,086 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00167% 27/1,614,026 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,386
Remaining individualsnot grpmax-eligible	0.0032%	31,244
East Asian	0.00223%	44,886
Admixed American	0.00167%	60,006
European (non-Finnish)	0.00127%	78,669

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.Arg155Cys
Coding: c.463C>T
MANE Select: NM_016356
dbSNP: rs368811969
Type: single nucleotide variant
Location: chr6:24301809 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 155: 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

For Isolated neonatal sclerosing cholangitis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

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DCDC2 p.Leu297Ter Pathogenic ★★ same condition
DCDC2 p.Met1Arg Pathogenic/Likely pathogenic ★★ ⚠ same condition
DCDC2 p.Ser128Ter Pathogenic/Likely pathogenic ★★ same condition
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DCDC2 p.Ala93Asp 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-arg155cys (accessed [today's date]).

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