Is DCDC2 p.Val475Met (c.1423G>A) pathogenic?

DCDC2 p.Val475Met (c.1423G>A) is classified Conflicting classifications of pathogenicity in DCDC2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2022-12-28). AlphaMissense: likely benign (0.2289); Rare (popmax 0.151%, afr); Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Val475Met (c.1423G>A)?

DCDC2 p.Val475Met (c.1423G>A) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66 (ClinVar).

How common is DCDC2 p.Val475Met (c.1423G>A) in the general population?

DCDC2 p.Val475Met (c.1423G>A) is rare (popmax 0.151%, 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.Val475Met (c.1423G>A)?

AlphaMissense predicts likely benign (score 0.2289) — an in-silico prediction, not a clinical call.

DCDC2 p.Val475Met

c.1423G>A · rs145154884 · VCV593401

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2289 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.151%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
AlphaMissense	0.2289	likely benign
REVEL	0.1	moderately benign-leaning
SaProt	LLR -8.31	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 1.5	GERP 1.5, phastCons 0.84
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	17.84	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 0.151% African / African-American · 113/74,922 alleles

Filtering AF 0.128% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.12%

Overall 0.0128% 206/1,611,036 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.151%	663
Ashkenazi Jewishnot grpmax-eligible	0.112%	895
Admixed American	0.0183%	5,450
Remaining individualsnot grpmax-eligible	0.016%	6,239
European (non-Finnish)	0.00314%	31,831
East Asian	0.00223%	44,804
South Asian	0.0011%	90,848

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.Val475Met
Coding: c.1423G>A
MANE Select: NM_016356
dbSNP: rs145154884
Type: single nucleotide variant
Location: chr6:24174738 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 475: 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

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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
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-val475met (accessed [today's date]).

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