Is CTSF p.Ser319Phe (c.956C>T) pathogenic?

CTSF p.Ser319Phe (c.956C>T) is classified Uncertain significance in CTSF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-11). AlphaMissense: likely pathogenic (0.9917); Very rare (popmax 0.0022%, sas); Associated with neuronal ceroid lipofuscinosis 13.

What condition is associated with CTSF p.Ser319Phe (c.956C>T)?

CTSF p.Ser319Phe (c.956C>T) is associated with neuronal ceroid lipofuscinosis 13 (ClinVar).

How common is CTSF p.Ser319Phe (c.956C>T) in the general population?

CTSF p.Ser319Phe (c.956C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about CTSF p.Ser319Phe (c.956C>T)?

AlphaMissense predicts likely pathogenic (score 0.9917) — an in-silico prediction, not a clinical call.

CTSF p.Ser319Phe

c.956C>T · rs1857917060 · VCV1978417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9917 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

neuronal ceroid lipofuscinosis 13

Computational evidence

Protein change
AlphaMissense	0.9917	likely pathogenic · top 1% in CTSF
REVEL	0.767	pathogenic-leaning
SaProt	LLR -15.81	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 4,550 bp · p 0.69 · regional, not allelic
Overall
CADD	32.0	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 0.0022% South Asian · 2/91,092 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000136%

Overall 0.00031% 5/1,613,826 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,546
European (non-Finnish)	0.000254%	393,328

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.Ser319Phe
Coding: c.956C>T
MANE Select: NM_003793
dbSNP: rs1857917060
Type: single nucleotide variant
Location: chr11:66565839 (GRCh38)
Gene constraint: LOEUF 1.296 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.78 · 1 PDB
Residue 319: 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 p.Ser319Ala Uncertain significance ★ ⚠ same residue
CTSF p.Ser319fs Pathogenic same residue
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

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-ser319phe (accessed [today's date]).

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