Is TPP1 p.Ser324fs (c.972_979del) pathogenic?

TPP1 p.Ser324fs (c.972979del) is classified Pathogenic in TPP1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-24). Very rare (popmax 0.000169%, nfe); Associated with neuronal ceroid lipofuscinosis 2.

What condition is associated with TPP1 p.Ser324fs (c.972_979del)?

TPP1 p.Ser324fs (c.972_979del) is associated with neuronal ceroid lipofuscinosis 2, autosomal recessive spinocerebellar ataxia 7 (ClinVar).

How common is TPP1 p.Ser324fs (c.972_979del) in the general population?

TPP1 p.Ser324fs (c.972_979del) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is CLN2 disease inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TPP1 p.Ser324fs

c.972_979del · rs778232650 · VCV188850

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

neuronal ceroid lipofuscinosis 2

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 8 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.9	GERP 1.3, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,956 alleles

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

Overall 0.000124% 2/1,613,792 alleles · very rare exomes 2/1,461,754 · genomes 0/152,038 · joint denominator

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: TPP1
Protein: p.Ser324fs
Coding: c.972_979del
MANE Select: NM_000391
dbSNP: rs778232650
Type: Deletion
Location: chr11:6616411 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 324: the peptidase s53 domain; a β-strand

Full TPP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal recessive spinocerebellar ataxia 7

For CLN2 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

TPP1 c.1363_1425+9del Pathogenic/Likely pathogenic ★★ same condition
TPP1 c.376_380+6del Pathogenic ★★ same condition
TPP1 c.90del Pathogenic/Likely pathogenic ★★ same condition
TPP1 p.Arg497fs Pathogenic/Likely pathogenic ★★ same condition
TPP1 p.Asn313fs Pathogenic ★★ same condition
TPP1 p.Gly501fs Pathogenic/Likely pathogenic ★★ same condition
TPP1 p.His491fs Pathogenic/Likely pathogenic ★★ same condition
TPP1 p.Leu49fs 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/tpp1-p-ser324fs (accessed [today's date]).

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