Is DCDC2 p.Pro273Ser (c.817C>T) pathogenic?

DCDC2 p.Pro273Ser (c.817C>T) is classified Conflicting classifications of pathogenicity in DCDC2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-09). AlphaMissense: likely benign (0.1101); Rare (popmax 0.185%, afr); Associated with autosomal recessive nonsyndromic hearing loss 66.

What condition is associated with DCDC2 p.Pro273Ser (c.817C>T)?

DCDC2 p.Pro273Ser (c.817C>T) is associated with autosomal recessive nonsyndromic hearing loss 66, isolated neonatal sclerosing cholangitis (ClinVar).

How common is DCDC2 p.Pro273Ser (c.817C>T) in the general population?

DCDC2 p.Pro273Ser (c.817C>T) is rare (popmax 0.185%, afr) (gnomAD).

What do computational predictors say about DCDC2 p.Pro273Ser (c.817C>T)?

AlphaMissense predicts likely benign (score 0.1101) — an in-silico prediction, not a clinical call.

DCDC2 p.Pro273Ser

c.817C>T · rs146787541 · VCV593556

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1101 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.185%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive nonsyndromic hearing loss 66

Computational evidence

Protein change
AlphaMissense	0.1101	likely benign
REVEL	0.195	benign-leaning
SaProt	LLR -6.21	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 6.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	23.1	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 0.185% African / African-American · 139/74,952 alleles

Filtering AF 0.16% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.151%

Overall 0.0104% 167/1,613,398 alleles · rare exomes 82/1,461,238 · genomes 85/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.185%	539
Middle Eastern	0.033%	3,029
Remaining individualsnot grpmax-eligible	0.032%	3,123
Admixed American	0.00333%	29,985
South Asian	0.0033%	30,317
European (non-Finnish)	8.48e-05%	1,179,638

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.Pro273Ser
Coding: c.817C>T
MANE Select: NM_016356
dbSNP: rs146787541
Type: single nucleotide variant
Location: chr6:24278154 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 273: 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: 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-pro273ser (accessed [today's date]).

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