Is DCDC2 p.Ser181Arg (c.543C>A) pathogenic?

DCDC2 p.Ser181Arg (c.543C>A) is classified Conflicting classifications of pathogenicity in DCDC2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-04-28). AlphaMissense: likely pathogenic (0.8881); Rare (popmax 0.492%, afr); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Ser181Arg (c.543C>A)?

DCDC2 p.Ser181Arg (c.543C>A) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66 (ClinVar).

How common is DCDC2 p.Ser181Arg (c.543C>A) in the general population?

DCDC2 p.Ser181Arg (c.543C>A) is rare (popmax 0.492%, 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.Ser181Arg (c.543C>A)?

AlphaMissense predicts likely pathogenic (score 0.8881) — an in-silico prediction, not a clinical call.

DCDC2 p.Ser181Arg

c.543C>A · rs141060456 · VCV594123

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8881 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.492%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
AlphaMissense	0.8881	likely pathogenic · top 10% in DCDC2
REVEL	0.68	pathogenic-leaning
SaProt	LLR -15.69	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.99	GERP -3.6
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	12.98	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 0.492% African / African-American · 369/75,010 alleles

Filtering AF 0.451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.434%

Overall 0.026% 419/1,614,036 alleles · rare exomes 197/1,461,836 · genomes 222/152,200 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.492%	203
Admixed American	0.0433%	2,308
Remaining individualsnot grpmax-eligible	0.0288%	3,472
European (non-Finnish)	0.000508%	196,666

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.Ser181Arg
Coding: c.543C>A
MANE Select: NM_016356
dbSNP: rs141060456
Type: single nucleotide variant
Location: chr6:24301729 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 181: 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

For Isolated neonatal sclerosing cholangitis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

DCDC2 p.Ser181= Conflicting classifications of pathogenicity ★ 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-ser181arg (accessed [today's date]).

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