Is DCDC2 p.Lys456Asn (c.1368A>T) pathogenic?

DCDC2 p.Lys456Asn (c.1368A>T) is classified Benign/Likely benign in DCDC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.2568); Common (popmax 44.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with autosomal recessive nonsyndromic hearing loss 66.

What condition is associated with DCDC2 p.Lys456Asn (c.1368A>T)?

DCDC2 p.Lys456Asn (c.1368A>T) is associated with autosomal recessive nonsyndromic hearing loss 66, isolated neonatal sclerosing cholangitis (ClinVar).

What do computational predictors say about DCDC2 p.Lys456Asn (c.1368A>T)?

AlphaMissense predicts likely benign (score 0.2568) — an in-silico prediction, not a clinical call.

DCDC2 p.Lys456Asn

Q: How common is DCDC2 p.Lys456Asn (c.1368A>T) in the general population?

DCDC2 p.Lys456Asn (c.1368A>T) is common (popmax 44.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1368A>T · rs9460973 · VCV508595

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.2568 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 44.7%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 66

Computational evidence

Protein change
AlphaMissense	0.2568	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -5.72	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 2.3	GERP -0.75, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	21.0	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 44.7% African / African-American · 33,429/74,800 alleles

Filtering AF 44.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 44.1%

Overall 4.87% 78,618/1,613,154 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	44.7%	2
Admixed American	5.94%	17
Remaining individualsnot grpmax-eligible	5.37%	19
Middle Eastern	3.98%	25
European (non-Finnish)	3.11%	32
Ashkenazi Jewishnot grpmax-eligible	2.74%	36
Finnishnot grpmax-eligible	0.392%	255
South Asian	0.249%	401
East Asian	0.00223%	44,832

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.Lys456Asn
Coding: c.1368A>T
MANE Select: NM_016356
dbSNP: rs9460973
Type: single nucleotide variant
Location: chr6:24174793 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 456: a UniProt-annotated variant site (in nsc); a UniProt-annotated variant site (in); the 'disordered' region

Full DCDC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive nonsyndromic hearing loss 66 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated neonatal sclerosing cholangitis

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-lys456asn (accessed [today's date]).

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