Is DCDC2 p.Arg403His (c.1208G>A) pathogenic?

DCDC2 p.Arg403His (c.1208G>A) is classified Benign/Likely benign in DCDC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0774); Rare (popmax 0.653%, afr); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Arg403His (c.1208G>A)?

DCDC2 p.Arg403His (c.1208G>A) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66 (ClinVar).

How common is DCDC2 p.Arg403His (c.1208G>A) in the general population?

DCDC2 p.Arg403His (c.1208G>A) is rare (popmax 0.653%, 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.Arg403His (c.1208G>A)?

AlphaMissense predicts likely benign (score 0.0774) — an in-silico prediction, not a clinical call.

DCDC2 p.Arg403His

c.1208G>A · rs139858268 · VCV466322

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0774 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.653%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
AlphaMissense	0.0774	likely benign
REVEL	0.028	moderately benign-leaning
SaProt	LLR -5.85	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 -2.8	GERP -2.4
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	4.992	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 0.653% African / African-American · 490/75,038 alleles

Filtering AF 0.605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.586%

Overall 0.0378% 610/1,614,202 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.653%	153
Admixed American	0.0533%	1,876
Remaining individualsnot grpmax-eligible	0.0448%	2,233
East Asian	0.0223%	4,488
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.00407%	24,584
South Asian	0.0011%	91,080

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.Arg403His
Coding: c.1208G>A
MANE Select: NM_016356
dbSNP: rs139858268
Type: single nucleotide variant
Location: chr6:24178448 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 403: 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.Arg403Cys 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-arg403his (accessed [today's date]).

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