Is DCDC2 p.Ile74= (c.222C>A) pathogenic?

DCDC2 p.Ile74= (c.222C>A) is classified Conflicting classifications of pathogenicity in DCDC2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-29). Ultra-rare (popmax 0.0825%, mid); Associated with autosomal recessive nonsyndromic hearing loss 66.

What condition is associated with DCDC2 p.Ile74= (c.222C>A)?

DCDC2 p.Ile74= (c.222C>A) is associated with autosomal recessive nonsyndromic hearing loss 66, isolated neonatal sclerosing cholangitis (ClinVar).

How common is DCDC2 p.Ile74= (c.222C>A) in the general population?

DCDC2 p.Ile74= (c.222C>A) is ultra-rare (popmax 0.0825%, mid) (gnomAD).

DCDC2 p.Ile74=

c.222C>A · rs138670560 · VCV502350

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0825%, mid)

Conditions

autosomal recessive nonsyndromic hearing loss 66

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.117	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP -1.9, phastCons 1
Overall
CADD	17.53	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0825% Middle Eastern · 5/6,062 alleles

Filtering AF 0.0427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.0227% 366/1,613,552 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0825%	1,212
South Asian	0.0549%	1,822
Remaining individualsnot grpmax-eligible	0.04%	2,500
European (non-Finnish)	0.023%	4,354
Admixed American	0.0217%	4,617
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
Finnishnot grpmax-eligible	0.00158%	63,368

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.Ile74=
Coding: c.222C>A
MANE Select: NM_016356
dbSNP: rs138670560
Type: single nucleotide variant
Location: chr6:24357529 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 74: the doublecortin 1 domain

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-ile74 (accessed [today's date]).

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