Is DCDC2 p.Lys249Gln (c.745A>C) pathogenic?

DCDC2 p.Lys249Gln (c.745A>C) is classified Uncertain significance in DCDC2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-01-31). AlphaMissense: likely benign (0.1772); Absent from gnomAD v4.1; Associated with DCDC2-related disorder.

What condition is associated with DCDC2 p.Lys249Gln (c.745A>C)?

DCDC2 p.Lys249Gln (c.745A>C) is associated with DCDC2-related disorder (ClinVar).

How common is DCDC2 p.Lys249Gln (c.745A>C) in the general population?

DCDC2 p.Lys249Gln (c.745A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DCDC2 p.Lys249Gln (c.745A>C)?

AlphaMissense predicts likely benign (score 0.1772) — an in-silico prediction, not a clinical call.

DCDC2 p.Lys249Gln

c.745A>C · rs2532381646 · VCV3057280

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1772 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

DCDC2-related disorder

Computational evidence

Protein change
AlphaMissense	0.1772	likely benign
REVEL	0.106	moderately benign-leaning
SaProt	LLR -9.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 0.71, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	25.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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.Lys249Gln
Coding: c.745A>C
MANE Select: NM_016356
dbSNP: rs2532381646
Type: single nucleotide variant
Location: chr6:24288866 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 249: 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

DCDC2-related disorder

Similar variants

DCDC2 c.705-2A>G Pathogenic ★★ same condition
DCDC2 c.557+1G>T Pathogenic ★ same condition
DCDC2 p.Gln448Lys Uncertain significance ★ ⚠ same condition
DCDC2 p.Gln417Ter Likely pathogenic same condition
DCDC2 p.Gly368Glu Uncertain significance ⚠ same condition
DCDC2 c.1326+6T>G Likely benign same condition
DCDC2 c.704+6T>C Likely benign same condition
DCDC2 c.*10A>G Likely benign 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-lys249gln (accessed [today's date]).

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