Is CLN5 p.Phe260fs (c.777_778del) pathogenic?

CLN5 p.Phe260fs (c.777778del) is classified Pathogenic/Likely pathogenic in CLN5 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2025-08-15). Ultra-rare (popmax 0.0167%, amr); Associated with CLN5-related disorder.

What condition is associated with CLN5 p.Phe260fs (c.777_778del)?

CLN5 p.Phe260fs (c.777_778del) is associated with CLN5-related disorder, neuronal ceroid lipofuscinosis 5, neuronal ceroid lipofuscinosis (ClinVar).

How common is CLN5 p.Phe260fs (c.777_778del) in the general population?

CLN5 p.Phe260fs (c.777_778del) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

CLN5 p.Phe260fs

c.777_778del · rs786204644 · VCV189038

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Conditions

CLN5-related disorder

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 (4 of 4) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.4	GERP 0.6, phastCons 1
Overall
CADD	33.0	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 0.0167% Admixed American · 10/60,000 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.000682% 11/1,613,982 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	6,000
Remaining individualsnot grpmax-eligible	0.0016%	62,482

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: CLN5
Protein: p.Phe260fs
Coding: c.777_778del
MANE Select: NM_006493
dbSNP: rs786204644
Type: Microsatellite
Location: chr13:77000667 (GRCh38)
Gene constraint: LOEUF 1.197 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05 · 1 PDB

Full CLN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

CLN5-related disorder

Also linked: neuronal ceroid lipofuscinosis 5 neuronal ceroid lipofuscinosis

Similar variants

CLN5 p.Leu309fs Pathogenic ★★ same condition
CLN5 p.Thr342_Tyr343insTer Pathogenic ★★ same condition
CLN5 c.173+13GC[6] Likely benign ★★ same condition
CLN5 p.Leu236fs Pathogenic ★ same condition
CLN5 p.Phe249fs Pathogenic ★ same condition
CLN5 p.Ser45fs Likely pathogenic ★ same condition
CLN5 p.16GA[3] Conflicting classifications of pathogenicity ★ same condition
CLN5 p.Phe260Leu Uncertain significance ★ ⚠ same residue

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/cln5-p-phe260fs (accessed [today's date]).

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