Is PPT1 p.Phe147Ser (c.440T>C) pathogenic?

PPT1 p.Phe147Ser (c.440T>C) is classified Uncertain significance in PPT1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-08-30). AlphaMissense: likely pathogenic (0.8293); Very rare (popmax 0.00267%, afr); Associated with Inborn genetic diseases.

What condition is associated with PPT1 p.Phe147Ser (c.440T>C)?

PPT1 p.Phe147Ser (c.440T>C) is associated with Inborn genetic diseases, neuronal ceroid lipofuscinosis 1 (ClinVar).

How common is PPT1 p.Phe147Ser (c.440T>C) in the general population?

PPT1 p.Phe147Ser (c.440T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PPT1 p.Phe147Ser (c.440T>C)?

AlphaMissense predicts likely pathogenic (score 0.8293) — an in-silico prediction, not a clinical call.

PPT1 p.Phe147Ser

c.440T>C · rs760784114 · VCV1007785

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8293	likely pathogenic
REVEL	0.696	pathogenic-leaning
SaProt	LLR -3.95	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 4.6	GERP -0.19, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 23 kb · p 0.052 · regional, not allelic
Overall
CADD	24.9	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 0.00267% African / African-American · 2/74,908 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000992% 16/1,613,040 alleles · very rare exomes 14/1,460,874 · genomes 2/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,454
European (non-Finnish)	0.00119%	84,222

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.Phe147Ser
Coding: c.440T>C
MANE Select: NM_000310
dbSNP: rs760784114
Type: single nucleotide variant
Location: chr1:40089506 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: neuronal ceroid lipofuscinosis 1

Similar variants

PPT1 p.Phe147= Likely benign ★ same residue
PPT1 p.Phe147fs Pathogenic ★ 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-phe147ser (accessed [today's date]).

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