Is TPP1 p.Ala348= (c.1044C>T) pathogenic?

TPP1 p.Ala348= (c.1044C>T) is classified Benign/Likely benign in TPP1 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-06-01). Low-frequency (popmax 1.45%, nfe); Associated with neuronal ceroid lipofuscinosis 2.

What condition is associated with TPP1 p.Ala348= (c.1044C>T)?

TPP1 p.Ala348= (c.1044C>T) is associated with neuronal ceroid lipofuscinosis 2, autosomal recessive spinocerebellar ataxia 7 (ClinVar).

How common is TPP1 p.Ala348= (c.1044C>T) in the general population?

TPP1 p.Ala348= (c.1044C>T) is low-frequency (popmax 1.45%, nfe) (gnomAD).

How is CLN2 disease inherited?

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

TPP1 p.Ala348=

c.1044C>T · rs35706972 · VCV130605

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.45%, nfe)

Conditions

neuronal ceroid lipofuscinosis 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -2.9
Overall
CADD	1.326	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.45% European (non-Finnish) · 17,073/1,179,940 alleles

Filtering AF 1.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.42%

Overall 1.25% 20,221/1,613,516 alleles · low-frequency exomes 18,748/1,461,284 · genomes 1,473/152,232 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.45%	69
Amishnot grpmax-eligible	1.32%	76
Ashkenazi Jewishnot grpmax-eligible	1.31%	76
Remaining individualsnot grpmax-eligible	1.26%	79
Finnishnot grpmax-eligible	1.2%	84
Middle Eastern	0.722%	139
South Asian	0.652%	153
Admixed American	0.636%	157
African / African-American	0.233%	429
East Asian	0.00223%	44,878

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.Ala348=
Coding: c.1044C>T
MANE Select: NM_000391
dbSNP: rs35706972
Type: single nucleotide variant
Location: chr11:6616346 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 348: an α-helix; the peptidase s53 domain

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 p.Ala348_Ala349del Uncertain significance same residue
TPP1 p.Ala348Asp Uncertain significance ★★ ⚠ same residue
TPP1 c.1075+2T>C Pathogenic/Likely pathogenic ★★ same condition
TPP1 c.1076-2A>G Pathogenic/Likely pathogenic ★★ same condition
TPP1 c.1076-2A>T Pathogenic ★★ same condition
TPP1 c.1146-1G>A Likely pathogenic ★★ same condition
TPP1 c.1425+1G>A Likely pathogenic ★★ same condition
TPP1 c.1551+1G>A 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-ala348 (accessed [today's date]).

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