Is CLN6 p.Pro297fs (c.890del) pathogenic?

CLN6 p.Pro297fs (c.890del) is classified Pathogenic/Likely pathogenic in CLN6 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-02-18). Very rare (popmax 0.000937%, nfe); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN6 p.Pro297fs (c.890del)?

CLN6 p.Pro297fs (c.890del) is associated with neuronal ceroid lipofuscinosis, ceroid lipofuscinosis, neuronal, 6A (ClinVar).

How common is CLN6 p.Pro297fs (c.890del) in the general population?

CLN6 p.Pro297fs (c.890del) is very rare (popmax 0.000937%, nfe) (gnomAD).

CLN6 p.Pro297fs

c.890del · rs154774639 · VCV68098

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000937%, nfe)

Conditions

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	escapes	premature termination codon in the last exon (7 of 7) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -5.1	GERP -4.1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000937% European (non-Finnish) · 11/1,173,536 alleles

Filtering AF 0.000503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000368%

Overall 0.000686% 11/1,602,566 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: CLN6
Protein: p.Pro297fs
Coding: c.890del
MANE Select: NM_017882
dbSNP: rs154774639
Type: Deletion
Location: chr15:68208186 (GRCh38)
Gene constraint: LOEUF 1.015 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.86
Residue 297: a UniProt-annotated variant site (in cln6)

Full CLN6 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

Also linked: ceroid lipofuscinosis, neuronal, 6A

Similar variants

CLN6 p.Ile153fs Pathogenic/Likely pathogenic ★★ same condition
CLN6 p.Phe120_Met122del Pathogenic/Likely pathogenic ★★ same condition
CLN6 p.Phe60fs Pathogenic/Likely pathogenic ★★ same condition
CLN6 c.297+19del Benign/Likely benign ★★ same condition
CLN6 p.Ala41fs Pathogenic ★ same condition
CLN6 p.Arg136fs Pathogenic ★ same condition
CLN6 p.Arg62fs Pathogenic ★ same condition
CLN6 p.Gly195fs 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/cln6-p-pro297fs (accessed [today's date]).

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