Is CTSO p.Asn125Lys (c.375C>A) pathogenic?

CTSO p.Asn125Lys (c.375C>A) is classified Uncertain significance in CTSO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-24). AlphaMissense: ambiguous (0.5116); Very rare (popmax 0.00474%, nfe).

How common is CTSO p.Asn125Lys (c.375C>A) in the general population?

CTSO p.Asn125Lys (c.375C>A) is very rare (popmax 0.00474%, nfe) (gnomAD).

What do computational predictors say about CTSO p.Asn125Lys (c.375C>A)?

AlphaMissense predicts ambiguous (score 0.5116) — an in-silico prediction, not a clinical call.

CTSO p.Asn125Lys

c.375C>A · VCV4657571

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5116 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00474%, nfe)

Computational evidence

Protein change
AlphaMissense	0.5116	ambiguous
REVEL	0.362	indeterminate
SaProt	LLR -12.79	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.5	GERP 1.6, phastCons 1
Overall
CADD	24.8	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 0.00474% European (non-Finnish) · 55/1,160,370 alleles

Filtering AF 0.00373% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00334%

Overall 0.00376% 59/1,569,256 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00496%	20,170
European (non-Finnish)grpmax	0.00474%	21,098
Finnishnot grpmax-eligible	0.00159%	63,060

Remaining individuals 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: CTSO
Protein: p.Asn125Lys
Coding: c.375C>A
MANE Select: NM_000396 · reported on NM_001334
Type: single nucleotide variant
Location: chr4:155942326 (GRCh38)
Structure: AlphaFold pLDDT 94.89 · 70 PDB

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

Similar variants

CTSK p.Gly125= Uncertain significance ★★ same residue
CTSK p.Gly125Glu Uncertain significance ⚠ same residue
CTSK p.Gly125fs Pathogenic ★ 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

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-asn125lys (accessed [today's date]).

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