Is CTSO p.Pro109Ser (c.325C>T) pathogenic?

CTSO p.Pro109Ser (c.325C>T) is classified Uncertain significance in CTSO (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-16). AlphaMissense: likely benign (0.2053); Very rare (popmax 0.00135%, afr).

How common is CTSO p.Pro109Ser (c.325C>T) in the general population?

CTSO p.Pro109Ser (c.325C>T) is very rare (popmax 0.00135%, afr) (gnomAD).

What do computational predictors say about CTSO p.Pro109Ser (c.325C>T)?

AlphaMissense predicts likely benign (score 0.2053) — an in-silico prediction, not a clinical call.

CTSO p.Pro109Ser

c.325C>T · VCV3837347

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2053 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00135%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2053	likely benign
REVEL	0.871	moderately pathogenic-leaning
SaProt	LLR -12.14	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.6, phastCons 1
Overall
CADD	26.6	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 0.00135% African / African-American · 1/73,908 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00197% 3/151,932 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00135%	73,908
European (non-Finnish)	0.00017%	587,630

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: CTSO
Protein: p.Pro109Ser
Coding: c.325C>T
MANE Select: NM_000396 · reported on NM_001334
Type: single nucleotide variant
Location: chr4:155942376 (GRCh38)
Structure: AlphaFold pLDDT 94.89 · 70 PDB

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

Similar variants

CTSO p.Pro109Leu Uncertain significance ★ ⚠ same residue
CTSK p.Pro109= Likely benign ★ same residue
CTSK c.121-1G>A Pathogenic/Likely pathogenic ★★ same type
CTSK c.121-2A>G Pathogenic/Likely pathogenic ★★ same type
CTSK c.244-29A>G Pathogenic/Likely pathogenic ★★ same type
CTSK c.244-2A>C Likely pathogenic ★★ same type
CTSK c.400-1G>C Likely pathogenic ★★ same type
CTSK c.784+1G>A Likely pathogenic ★★ same type

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/ctso-p-pro109ser (accessed [today's date]).

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