Is DCDC2 p.Val455Ala (c.1364T>C) pathogenic?

DCDC2 p.Val455Ala (c.1364T>C) is classified Uncertain significance in DCDC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-12). AlphaMissense: ambiguous (0.4052); Ultra-rare (popmax 0.0178%, eas); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Val455Ala (c.1364T>C)?

DCDC2 p.Val455Ala (c.1364T>C) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66, nephronophthisis 19 (ClinVar).

How common is DCDC2 p.Val455Ala (c.1364T>C) in the general population?

DCDC2 p.Val455Ala (c.1364T>C) is ultra-rare (popmax 0.0178%, eas) (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.Val455Ala (c.1364T>C)?

AlphaMissense predicts ambiguous (score 0.4052) — an in-silico prediction, not a clinical call.

DCDC2 p.Val455Ala

c.1364T>C · rs763350514 · VCV594461

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4052 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
AlphaMissense	0.4052	ambiguous
REVEL	0.076	moderately benign-leaning
SaProt	LLR -7.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	25.8	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 0.0178% East Asian · 8/44,838 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000558% 9/1,613,456 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,605
Remaining individualsnot grpmax-eligible	0.0016%	62,460

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.Val455Ala
Coding: c.1364T>C
MANE Select: NM_016356
dbSNP: rs763350514
Type: single nucleotide variant
Location: chr6:24174797 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 455: 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 nephronophthisis 19

For Isolated neonatal sclerosing cholangitis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

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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
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-val455ala (accessed [today's date]).

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