Is PPT1 p.Ser293Pro (c.877T>C) pathogenic?

PPT1 p.Ser293Pro (c.877T>C) is classified Uncertain significance in PPT1 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-04-16). AlphaMissense: likely benign (0.1585); Very rare (popmax 0.00333%, amr); Associated with neuronal ceroid lipofuscinosis 1.

What condition is associated with PPT1 p.Ser293Pro (c.877T>C)?

PPT1 p.Ser293Pro (c.877T>C) is associated with neuronal ceroid lipofuscinosis 1 (ClinVar).

How common is PPT1 p.Ser293Pro (c.877T>C) in the general population?

PPT1 p.Ser293Pro (c.877T>C) is very rare (popmax 0.00333%, amr) (gnomAD).

How is CLN1 disease inherited?

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

What do computational predictors say about PPT1 p.Ser293Pro (c.877T>C)?

AlphaMissense predicts likely benign (score 0.1585) — an in-silico prediction, not a clinical call.

PPT1 p.Ser293Pro

c.877T>C · rs1304668396 · VCV991803

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1585 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuronal ceroid lipofuscinosis 1

Computational evidence

Protein change
AlphaMissense	0.1585	likely benign
REVEL	0.572	indeterminate
SaProt	LLR -8.67	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 23 kb · p 0.052 · regional, not allelic
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,026 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000124% 2/1,614,064 alleles · very rare exomes 2/1,461,738 · genomes 0/152,326 · 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: PPT1
Protein: p.Ser293Pro
Coding: c.877T>C
MANE Select: NM_000310
dbSNP: rs1304668396
Type: single nucleotide variant
Location: chr1:40074105 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.05 · 1 PDB

Full PPT1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

neuronal ceroid lipofuscinosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CLN1 disease (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy

Similar variants

PPT1 p.Ser293Phe Uncertain significance ★★ ⚠ same residue
PPT1 p.Ser293= Likely benign ★★ same residue
PPT1 c.234+1G>A Pathogenic ★★ same condition
PPT1 c.362+1G>A Likely pathogenic ★★ same condition
PPT1 c.433+1G>A Pathogenic ★★ same condition
PPT1 c.627+1G>T Likely pathogenic ★★ same condition
PPT1 c.628-1G>T Pathogenic ★★ same condition
PPT1 c.628-2A>G 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/ppt1-p-ser293pro (accessed [today's date]).

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