Is DCDC2 p.Pro152Ala (c.454C>G) pathogenic?

DCDC2 p.Pro152Ala (c.454C>G) is classified Benign/Likely benign in DCDC2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1332); Common (popmax 5.33%, sas) — too common for a highly-penetrant pathogenic allele; Associated with isolated neonatal sclerosing cholangitis.

What condition is associated with DCDC2 p.Pro152Ala (c.454C>G)?

DCDC2 p.Pro152Ala (c.454C>G) is associated with isolated neonatal sclerosing cholangitis, autosomal recessive nonsyndromic hearing loss 66 (ClinVar).

How is Isolated neonatal sclerosing cholangitis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DCDC2 p.Pro152Ala (c.454C>G)?

AlphaMissense predicts likely benign (score 0.1332) — an in-silico prediction, not a clinical call.

DCDC2 p.Pro152Ala

Q: How common is DCDC2 p.Pro152Ala (c.454C>G) in the general population?

DCDC2 p.Pro152Ala (c.454C>G) is common (popmax 5.33%, sas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.454C>G · rs33914824 · VCV466326

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1332 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.33%, sas) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

isolated neonatal sclerosing cholangitis

Computational evidence

Protein change
AlphaMissense	0.1332	likely benign
REVEL	0.441	indeterminate
SaProt	LLR -10.93	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 183 kb · p 0.62 · regional, not allelic
Overall
CADD	25.9	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 5.33% South Asian · 4,854/91,076 alleles

Filtering AF 5.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.15%

Overall 3.91% 63,178/1,614,066 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	9.56%	10
Ashkenazi Jewishnot grpmax-eligible	5.8%	17
South Asiangrpmax	5.33%	19
Middle Eastern	5.31%	19
Remaining individualsnot grpmax-eligible	4.27%	23
African / African-American	4.13%	24
European (non-Finnish)	3.98%	25
Admixed American	2.8%	36
Finnishnot grpmax-eligible	1.7%	59
East Asian	1.66%	60

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro152Ala
Coding: c.454C>G
MANE Select: NM_016356
dbSNP: rs33914824
Type: single nucleotide variant
Location: chr6:24301818 (GRCh38)
Gene constraint: LOEUF 1.062 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.93 · 1 PDB
Residue 152: a UniProt-annotated variant site (in); the doublecortin 2 domain

Full DCDC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

isolated neonatal sclerosing cholangitis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive nonsyndromic hearing loss 66

For Isolated neonatal sclerosing cholangitis (Orphanet):

Inheritance: Autosomal recessive
Onset: Neonatal

Similar variants

DCDC2 p.Pro152= 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
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-pro152ala (accessed [today's date]).

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