Is PPT1 p.Ser21Phe (c.62C>T) pathogenic?

PPT1 p.Ser21Phe (c.62C>T) is classified Uncertain significance in PPT1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-08-27). AlphaMissense: likely benign (0.1345); Very rare (popmax 0.00119%, nfe); Associated with neuronal ceroid lipofuscinosis 1.

What condition is associated with PPT1 p.Ser21Phe (c.62C>T)?

PPT1 p.Ser21Phe (c.62C>T) is associated with neuronal ceroid lipofuscinosis 1 (ClinVar).

How common is PPT1 p.Ser21Phe (c.62C>T) in the general population?

PPT1 p.Ser21Phe (c.62C>T) is very rare (popmax 0.00119%, nfe) (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.Ser21Phe (c.62C>T)?

AlphaMissense predicts likely benign (score 0.1345) — an in-silico prediction, not a clinical call.

PPT1 p.Ser21Phe

c.62C>T · rs796052922 · VCV206637

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1345 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00119%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 1

Computational evidence

Protein change
AlphaMissense	0.1345	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -11.07	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 0.076, phastCons 0.01
Regional constraint	o/e 0.90	unconstrained · MANE · 23 kb · p 0.052 · regional, not allelic
Overall
CADD	16.48	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 0.00119% European (non-Finnish) · 14/1,179,982 alleles

Filtering AF 0.000688% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000929% 15/1,614,006 alleles · very rare exomes 8/1,461,784 · genomes 7/152,222 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00156%	64,038
European (non-Finnish)grpmax	0.00119%	84,284

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser21Phe
Coding: c.62C>T
MANE Select: NM_000310
dbSNP: rs796052922
Type: single nucleotide variant
Location: chr1:40097177 (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.Ser21= 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
PPT1 c.727-2A>T 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-ser21phe (accessed [today's date]).

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