Is DNAJC5 p.Pro175Leu (c.524C>T) pathogenic?

DNAJC5 p.Pro175Leu (c.524C>T) is classified Conflicting classifications of pathogenicity in DNAJC5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-20). AlphaMissense: likely pathogenic (0.9864); Ultra-rare (popmax 0.0228%, nfe); Associated with ceroid lipofuscinosis, neuronal, 4 (Kufs type).

What condition is associated with DNAJC5 p.Pro175Leu (c.524C>T)?

DNAJC5 p.Pro175Leu (c.524C>T) is associated with ceroid lipofuscinosis, neuronal, 4 (Kufs type), neuronal ceroid lipofuscinosis (ClinVar).

How common is DNAJC5 p.Pro175Leu (c.524C>T) in the general population?

DNAJC5 p.Pro175Leu (c.524C>T) is ultra-rare (popmax 0.0228%, nfe) (gnomAD).

What do computational predictors say about DNAJC5 p.Pro175Leu (c.524C>T)?

AlphaMissense predicts likely pathogenic (score 0.9864) — an in-silico prediction, not a clinical call.

DNAJC5 p.Pro175Leu

c.524C>T · rs761982169 · VCV431814

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9864 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0228%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ceroid lipofuscinosis, neuronal, 4 (Kufs type)

Computational evidence

Protein change
AlphaMissense	0.9864	likely pathogenic
REVEL	0.705	pathogenic-leaning
SaProt	LLR -11.70	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.5, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 714 bp · p 0.018 · regional, not allelic
Overall
CADD	31.0	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 0.0228% European (non-Finnish) · 266/1,166,688 alleles

Filtering AF 0.0205% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.0173% 273/1,576,202 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0228%	4,386
Admixed American	0.00529%	18,904
South Asian	0.00231%	43,220
Remaining individualsnot grpmax-eligible	0.00163%	61,342
African / African-American	0.00136%	73,724

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: DNAJC5
Protein: p.Pro175Leu
Coding: c.524C>T
MANE Select: NM_025219
dbSNP: rs761982169
Type: single nucleotide variant
Location: chr20:63931495 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.09 · 2 PDB

Full DNAJC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ceroid lipofuscinosis, neuronal, 4 (Kufs type) — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis

For CLN4 disease (Orphanet):

Onset: Adult

Similar variants

DNAJC5 p.Pro175= Likely benign ★★ same residue
DNAJC5 p.Leu115Arg Pathogenic ★★ same condition
DNAJC5 c.-109A>G Uncertain significance ★★ same condition
DNAJC5 c.-11-2A>G Uncertain significance ★★ same condition
DNAJC5 p.Ala176Val Uncertain significance ★★ ⚠ same condition
DNAJC5 p.Ala26Thr Uncertain significance ★★ ⚠ same condition
DNAJC5 p.Ala54Thr Uncertain significance ★★ ⚠ same condition
DNAJC5 p.Ala54Val 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/dnajc5-p-pro175leu (accessed [today's date]).

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