Is CLN3 p.His65fs (c.191_192insTGGC) pathogenic?

CLN3 p.His65fs (c.191192insTGGC) is classified Likely pathogenic in CLN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-31). Associated with juvenile neuronal ceroid lipofuscinosis.

What condition is associated with CLN3 p.His65fs (c.191_192insTGGC)?

CLN3 p.His65fs (c.191_192insTGGC) is associated with juvenile neuronal ceroid lipofuscinosis (ClinVar).

CLN3 p.His65fs

c.191_192insTGGC · VCV4817044

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

juvenile neuronal ceroid lipofuscinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 4 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.61	GERP -3.3, phastCons 0.81

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: CLN3
Protein: p.His65fs
Coding: c.191_192insTGGC
MANE Select: NM_001042432
Type: Insertion
Location: chr16:28489320 (GRCh38)
Gene constraint: LOEUF 1.022 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 81.81

Full CLN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Similar variants

CLN3 c.1197+1G>A Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.222+1G>A Likely pathogenic ★★ same condition
CLN3 c.375-2del Likely pathogenic ★★ same condition
CLN3 c.46+1G>A Likely pathogenic ★★ same condition
CLN3 c.461-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.533+1G>C Pathogenic ★★ same condition
CLN3 c.534-2A>G Pathogenic/Likely pathogenic ★★ same condition
CLN3 c.678-2A>G Pathogenic/Likely pathogenic ★★ 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/cln3-p-his65fs (accessed [today's date]).

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