Is CLN5 p.Ser49fs (c.144dup) pathogenic?

CLN5 p.Ser49fs (c.144dup) is classified Pathogenic/Likely pathogenic in CLN5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-06-22). Very rare (popmax 0.00173%, amr); Associated with neuronal ceroid lipofuscinosis.

What condition is associated with CLN5 p.Ser49fs (c.144dup)?

CLN5 p.Ser49fs (c.144dup) is associated with neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis 5 (ClinVar).

How common is CLN5 p.Ser49fs (c.144dup) in the general population?

CLN5 p.Ser49fs (c.144dup) is very rare (popmax 0.00173%, amr) (gnomAD).

CLN5 p.Ser49fs

c.144dup · rs386833970 · VCV56532

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00173%, amr)

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	predicted	premature termination codon in exon 1 of 4
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2.1	GERP -2.4

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00173% Admixed American · 1/57,904 alleles

Overall 6.96e-05% 1/1,436,028 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: CLN5
Protein: p.Ser49fs
Coding: c.144dup
MANE Select: NM_006493
dbSNP: rs386833970
Type: Duplication
Location: chr13:76992238 (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

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

Also linked: neuronal ceroid lipofuscinosis 5

Similar variants

CLN5 p.Asn240Ter Pathogenic/Likely pathogenic ★★ same condition
CLN5 p.Asp172fs Pathogenic/Likely pathogenic ★★ same condition
CLN5 p.His148fs Pathogenic/Likely pathogenic ★★ same condition
CLN5 p.Trp175fs Pathogenic ★★ same condition
CLN5 c.566-8dup Benign/Likely benign ★★ same condition
CLN5 p.Asn255fs Pathogenic ★ same condition
CLN5 p.Glu12fs Likely pathogenic ★ same condition
CLN5 p.Glu219fs 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/cln5-p-ser49fs (accessed [today's date]).

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