Is CTSF p.Leu428Pro (c.1283T>C) pathogenic?

CTSF p.Leu428Pro (c.1283T>C) is classified Uncertain significance in CTSF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-12-25). AlphaMissense: likely pathogenic (0.6613); Very rare (popmax 0.0012%, nfe); Associated with neuronal ceroid lipofuscinosis 13.

What condition is associated with CTSF p.Leu428Pro (c.1283T>C)?

CTSF p.Leu428Pro (c.1283T>C) is associated with neuronal ceroid lipofuscinosis 13 (ClinVar).

How common is CTSF p.Leu428Pro (c.1283T>C) in the general population?

CTSF p.Leu428Pro (c.1283T>C) is very rare (popmax 0.0012%, nfe) (gnomAD).

What do computational predictors say about CTSF p.Leu428Pro (c.1283T>C)?

AlphaMissense predicts likely pathogenic (score 0.6613) — an in-silico prediction, not a clinical call.

CTSF p.Leu428Pro

c.1283T>C · VCV3342994

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0012%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

neuronal ceroid lipofuscinosis 13

Computational evidence

Protein change
AlphaMissense	0.6613	likely pathogenic
REVEL	0.541	indeterminate
SaProt	LLR -11.28	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.8, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,550 bp · p 0.69 · regional, not allelic
Overall
CADD	27.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0012% European (non-Finnish) · 14/1,170,126 alleles

Filtering AF 0.000694% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000543%

Overall 0.000879% 14/1,592,678 alleles · very rare

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: CTSF
Protein: p.Leu428Pro
Coding: c.1283T>C
MANE Select: NM_003793
Type: single nucleotide variant
Location: chr11:66564596 (GRCh38)
Gene constraint: LOEUF 1.296 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.78 · 1 PDB
Residue 428: a disulfide bond

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

Disease context

neuronal ceroid lipofuscinosis 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CLN13 disease (Orphanet):

Onset: Adolescent, Adult, Childhood, Elderly

Similar variants

CTSF c.1045+1G>T Likely pathogenic ★★ same condition
CTSF p.Ala22Ser Uncertain significance ★★ ⚠ same condition
CTSF p.Arg196Gln Uncertain significance ★★ ⚠ same condition
CTSF p.Arg205Trp Uncertain significance ★★ ⚠ same condition
CTSF p.Arg413Cys Uncertain significance ★★ ⚠ same condition
CTSF p.Gly415Arg Uncertain significance ★★ ⚠ same condition
CTSF p.Gly439Ser Uncertain significance ★★ ⚠ same condition
CTSF p.Leu7Phe Uncertain significance ★★ ⚠ 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/ctsf-p-leu428pro (accessed [today's date]).

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