Is TPP1 p.Ser331Phe (c.992C>T) pathogenic?

TPP1 p.Ser331Phe (c.992C>T) is classified Uncertain significance in TPP1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-09-05). AlphaMissense: likely pathogenic (0.6282); Very rare (popmax 0.000169%, nfe); Associated with neuronal ceroid lipofuscinosis 2.

What condition is associated with TPP1 p.Ser331Phe (c.992C>T)?

TPP1 p.Ser331Phe (c.992C>T) is associated with neuronal ceroid lipofuscinosis 2 (ClinVar).

How common is TPP1 p.Ser331Phe (c.992C>T) in the general population?

TPP1 p.Ser331Phe (c.992C>T) 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.

What do computational predictors say about TPP1 p.Ser331Phe (c.992C>T)?

AlphaMissense predicts likely pathogenic (score 0.6282) — an in-silico prediction, not a clinical call.

TPP1 p.Ser331Phe

c.992C>T · rs755386210 · VCV207585

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.6282 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 2

Computational evidence

Protein change
AlphaMissense	0.6282	likely pathogenic
REVEL	0.758	pathogenic-leaning
SaProt	LLR -7.57	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 4,851 bp · p 0.14 · regional, not allelic
Overall
CADD	27.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,014 alleles

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

Overall 0.000124% 2/1,613,998 alleles · very rare exomes 2/1,461,700 · genomes 0/152,298 · 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.Ser331Phe
Coding: c.992C>T
MANE Select: NM_000391
dbSNP: rs755386210
Type: single nucleotide variant
Location: chr11:6616398 (GRCh38)
Gene constraint: LOEUF 0.78 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.70 · 2 PDB
Residue 331: the peptidase s53 domain; an α-helix

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

For CLN2 disease (Orphanet):

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

Similar variants

TPP1 p.Ser331Tyr Uncertain significance ★ ⚠ same residue
TPP1 p.Ser331Cys Uncertain significance ★★ ⚠ same residue
TPP1 p.Ser331= Likely benign ★ 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

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-ser331phe (accessed [today's date]).

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