Is DNAJC5 p.Leu116Phe (c.346C>T) pathogenic?

DNAJC5 p.Leu116Phe (c.346C>T) is classified Uncertain significance in DNAJC5 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-13). AlphaMissense: likely benign (0.2504); Very rare (popmax 0.000169%, nfe); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with DNAJC5 p.Leu116Phe (c.346C>T)?

DNAJC5 p.Leu116Phe (c.346C>T) is associated with neuronal ceroid lipofuscinosis (ClinVar).

How common is DNAJC5 p.Leu116Phe (c.346C>T) in the general population?

DNAJC5 p.Leu116Phe (c.346C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about DNAJC5 p.Leu116Phe (c.346C>T)?

AlphaMissense predicts likely benign (score 0.2504) — an in-silico prediction, not a clinical call.

DNAJC5 p.Leu116Phe

c.346C>T · rs2053663677 · VCV1433552

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2504 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis

Computational evidence

Protein change
AlphaMissense	0.2504	likely benign
REVEL	0.101	moderately benign-leaning
SaProt	LLR -7.87	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 4.1	GERP -0.19, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 714 bp · p 0.018 · regional, not allelic
Overall
CADD	21.3	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 0.000169% European (non-Finnish) · 2/1,179,982 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,210 alleles · very 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: DNAJC5
Protein: p.Leu116Phe
Coding: c.346C>T
MANE Select: NM_025219
dbSNP: rs2053663677
Type: single nucleotide variant
Location: chr20:63930875 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.09 · 2 PDB
Residue 116: a UniProt-annotated variant site (in cln4b; results in near absence of palmitoylated monomeric forms of the protein and formation of high molecular mass aggregates with diffuse intracellular localization)

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

Disease context

neuronal ceroid lipofuscinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DNAJC5 p.Leu116del Pathogenic ★★ same residue
DNAJC5 p.Leu116Arg Pathogenic ★ same residue
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
DNAJC5 p.Ala63Thr Uncertain significance ★★ ⚠ same condition
DNAJC5 p.Arg164Lys 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-leu116phe (accessed [today's date]).

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