Is DCDC2 p.Ala324fs (c.970dup) pathogenic?

DCDC2 p.Ala324fs (c.970dup) is classified Pathogenic/Likely pathogenic in DCDC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2023-09-20). Very rare (popmax 0.00458%, nfe); Associated with autosomal recessive nonsyndromic hearing loss 66.

What condition is associated with DCDC2 p.Ala324fs (c.970dup)?

DCDC2 p.Ala324fs (c.970dup) is associated with autosomal recessive nonsyndromic hearing loss 66, nephronophthisis 19, isolated neonatal sclerosing cholangitis (ClinVar).

How common is DCDC2 p.Ala324fs (c.970dup) in the general population?

DCDC2 p.Ala324fs (c.970dup) is very rare (popmax 0.00458%, nfe) (gnomAD).

DCDC2 p.Ala324fs

c.970dup · rs774115675 · VCV595088

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00458%, nfe)

Conditions

autosomal recessive nonsyndromic hearing loss 66

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 8 of 10
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Overall
CADD	35.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00458% European (non-Finnish) · 54/1,179,978 alleles

Filtering AF 0.00358% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00321%

Overall 0.00341% 55/1,613,920 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00458%	21,851
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Ala324fs
Coding: c.970dup
MANE Select: NM_016356
dbSNP: rs774115675
Type: Duplication
Location: chr6:24205054 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 324: 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

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

Also linked: nephronophthisis 19 isolated neonatal sclerosing cholangitis

Similar variants

DCDC2 p.Ala324Ser Uncertain significance ★ ⚠ same residue
DCDC2 p.Ile177fs Pathogenic ★★ same condition
DCDC2 c.349-16dup Benign/Likely benign ★★ same condition
DCDC2 p.Val184fs Likely pathogenic ★ same condition
DCDC2 c.760-16dup Uncertain significance ★ same condition
DCDC2 c.294-2A>G Pathogenic ★★ same condition
DCDC2 c.349-2A>G Pathogenic ★★ same condition
DCDC2 c.705-2A>G Pathogenic ★★ 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-ala324fs (accessed [today's date]).

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