Is DCDC2 p.Thr229Ala (c.685A>G) pathogenic?

DCDC2 p.Thr229Ala (c.685A>G) is classified Uncertain significance in DCDC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-02-23). AlphaMissense: likely benign (0.0605); Ultra-rare (popmax 0.0133%, afr); Associated with autosomal recessive nonsyndromic hearing loss 66.

What condition is associated with DCDC2 p.Thr229Ala (c.685A>G)?

DCDC2 p.Thr229Ala (c.685A>G) is associated with autosomal recessive nonsyndromic hearing loss 66, nephronophthisis 19, isolated neonatal sclerosing cholangitis (ClinVar).

How common is DCDC2 p.Thr229Ala (c.685A>G) in the general population?

DCDC2 p.Thr229Ala (c.685A>G) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about DCDC2 p.Thr229Ala (c.685A>G)?

AlphaMissense predicts likely benign (score 0.0605) — an in-silico prediction, not a clinical call.

DCDC2 p.Thr229Ala

c.685A>G · rs1043649931 · VCV1035839

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0605 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 66

Computational evidence

Protein change
AlphaMissense	0.0605	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.18	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 -0.09	GERP -0.72, phastCons 0.001
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	6.745	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

Grpmax group 0.0133% African / African-American · 10/74,908 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.00062% 10/1,613,660 alleles · ultra-rare

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.Thr229Ala
Coding: c.685A>G
MANE Select: NM_016356
dbSNP: rs1043649931
Type: single nucleotide variant
Location: chr6:24290951 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 229: 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: nephronophthisis 19 isolated neonatal sclerosing cholangitis

Similar variants

DCDC2 p.Thr229Arg Uncertain significance ★ ⚠ same residue
DCDC2 p.Thr229Met Uncertain significance ★ ⚠ same residue
DCDC2 p.Thr229= Likely benign ★ 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

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-thr229ala (accessed [today's date]).

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