Is DCDC2 p.Lys227Met (c.680A>T) pathogenic?

DCDC2 p.Lys227Met (c.680A>T) is classified Uncertain significance in DCDC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-18). AlphaMissense: ambiguous (0.5598); Absent from gnomAD v4.1; Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Lys227Met (c.680A>T)?

DCDC2 p.Lys227Met (c.680A>T) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66 (ClinVar).

How common is DCDC2 p.Lys227Met (c.680A>T) in the general population?

DCDC2 p.Lys227Met (c.680A>T) is absent from gnomAD v4.1 (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.Lys227Met (c.680A>T)?

AlphaMissense predicts ambiguous (score 0.5598) — an in-silico prediction, not a clinical call.

DCDC2 p.Lys227Met

c.680A>T · VCV4790307

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5598 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
AlphaMissense	0.5598	ambiguous
REVEL	0.65	pathogenic-leaning
SaProt	LLR -13.12	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	23.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DCDC2
Protein: p.Lys227Met
Coding: c.680A>T
MANE Select: NM_016356
Type: single nucleotide variant
Location: chr6:24290956 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 227: a UniProt-annotated variant site (in nsc)

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 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
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-lys227met (accessed [today's date]).

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