Is CTSZ p.Ala18Ser (c.52G>T) pathogenic?

CTSZ p.Ala18Ser (c.52G>T) is classified Uncertain significance in CTSZ (ClinVar, Single submitter, 1 submitter; last evaluated 2021-11-10). AlphaMissense: likely benign (0.1292); Very rare (popmax 0.00072%, nfe).

How common is CTSZ p.Ala18Ser (c.52G>T) in the general population?

CTSZ p.Ala18Ser (c.52G>T) is very rare (popmax 0.00072%, nfe) (gnomAD).

What do computational predictors say about CTSZ p.Ala18Ser (c.52G>T)?

AlphaMissense predicts likely benign (score 0.1292) — an in-silico prediction, not a clinical call.

CTSZ p.Ala18Ser

c.52G>T · rs1225063145 · VCV2223851

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1292 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00072%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1292	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -8.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.85	GERP -0.6, phastCons 0.97
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.27 · regional, not allelic
Overall
CADD	15.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00072% European (non-Finnish) · 8/1,111,542 alleles

Filtering AF 0.00031% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000224%

Overall 0.000548% 8/1,459,546 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: CTSZ
Protein: p.Ala18Ser
Coding: c.52G>T
MANE Select: NM_001336
dbSNP: rs1225063145
Type: single nucleotide variant
Location: chr20:59007077 (GRCh38)
Gene constraint: LOEUF 1.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.35 · 2 PDB

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

Similar variants

CTSZ p.Ala18Val Uncertain significance ★ ⚠ same residue
CTSZ p.Gly191Arg Benign ★★ ⚠ same type
CTSZ p.Leu196Pro Benign/Likely benign ★★ same type
CTSZ p.Thr226Ser Benign ★★ ⚠ same type
CTSZ p.Ala144Thr Uncertain significance ★ ⚠ same type
CTSZ p.Ala60Glu Uncertain significance ★ ⚠ same type
CTSZ p.Ala60Val Uncertain significance ★ ⚠ same type
CTSZ p.Arg104Gln Uncertain significance ★ ⚠ 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/ctsz-p-ala18ser (accessed [today's date]).

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