Is DCDC2 p.Arg232Ser (c.696G>T) pathogenic?

DCDC2 p.Arg232Ser (c.696G>T) is classified Uncertain significance in DCDC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-29). AlphaMissense: ambiguous (0.5195); Ultra-rare (popmax 0.0627%, sas); Associated with autosomal recessive nonsyndromic hearing loss 66.

What condition is associated with DCDC2 p.Arg232Ser (c.696G>T)?

DCDC2 p.Arg232Ser (c.696G>T) is associated with autosomal recessive nonsyndromic hearing loss 66, isolated neonatal sclerosing cholangitis (ClinVar).

How common is DCDC2 p.Arg232Ser (c.696G>T) in the general population?

DCDC2 p.Arg232Ser (c.696G>T) is ultra-rare (popmax 0.0627%, sas) (gnomAD).

What do computational predictors say about DCDC2 p.Arg232Ser (c.696G>T)?

AlphaMissense predicts ambiguous (score 0.5195) — an in-silico prediction, not a clinical call.

DCDC2 p.Arg232Ser

c.696G>T · rs758802517 · VCV2035476

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5195 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0627%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

autosomal recessive nonsyndromic hearing loss 66

Computational evidence

Protein change
AlphaMissense	0.5195	ambiguous
REVEL	0.162	moderately benign-leaning
SaProt	LLR -11.46	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -1.4, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	20.2	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 0.0627% South Asian · 57/90,916 alleles

Filtering AF 0.0497% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.045%

Overall 0.00391% 63/1,613,204 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0627%	1,595
Admixed American	0.00167%	59,742
European (non-Finnish)	0.000424%	235,964

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.Arg232Ser
Coding: c.696G>T
MANE Select: NM_016356
dbSNP: rs758802517
Type: single nucleotide variant
Location: chr6:24290940 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 232: a UniProt-annotated variant site (in nsc)

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 p.Arg232= Conflicting classifications of pathogenicity ★ same residue
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

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-arg232ser (accessed [today's date]).

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