Is DNAJC5 p.Thr146= (c.438G>A) pathogenic?

DNAJC5 p.Thr146= (c.438G>A) is classified Conflicting classifications of pathogenicity in DNAJC5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-12-30). Very rare (popmax 0.0022%, sas); Associated with ceroid lipofuscinosis, neuronal, 4 (Kufs type).

What condition is associated with DNAJC5 p.Thr146= (c.438G>A)?

DNAJC5 p.Thr146= (c.438G>A) is associated with ceroid lipofuscinosis, neuronal, 4 (Kufs type), neuronal ceroid lipofuscinosis (ClinVar).

How common is DNAJC5 p.Thr146= (c.438G>A) in the general population?

DNAJC5 p.Thr146= (c.438G>A) is very rare (popmax 0.0022%, sas) (gnomAD).

DNAJC5 p.Thr146=

c.438G>A · rs746222594 · VCV339357

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

ceroid lipofuscinosis, neuronal, 4 (Kufs type)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.8	GERP -4.3
Overall
CADD	1.546	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,090 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.000205% 3/1,461,782 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,545
Admixed American	0.00167%	60,030

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.Thr146=
Coding: c.438G>A
MANE Select: NM_025219
dbSNP: rs746222594
Type: single nucleotide variant
Location: chr20:63930967 (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.Thr146Met Uncertain significance ★★ ⚠ same residue
DNAJC5 p.Thr146Leu Uncertain significance ★ same residue
DNAJC5 p.Thr146Ala Uncertain significance ★ ⚠ 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

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-thr146 (accessed [today's date]).

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