Is CTSZ p.Arg52Trp (c.154C>T) pathogenic?

CTSZ p.Arg52Trp (c.154C>T) is classified Uncertain significance in CTSZ (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-05). AlphaMissense: ambiguous (0.4018); Very rare (popmax 0.00267%, afr).

How common is CTSZ p.Arg52Trp (c.154C>T) in the general population?

CTSZ p.Arg52Trp (c.154C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CTSZ p.Arg52Trp (c.154C>T)?

AlphaMissense predicts ambiguous (score 0.4018) — an in-silico prediction, not a clinical call.

CTSZ p.Arg52Trp

c.154C>T · VCV3270250

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4018 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4018	ambiguous
REVEL	0.221	benign-leaning
SaProt	LLR -15.27	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP -0.29, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.27 · regional, not allelic
Overall
CADD	28.5	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 0.00267% African / African-American · 2/74,934 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00136% 22/1,612,154 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,467
European (non-Finnish)	0.0017%	58,986

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.Arg52Trp
Coding: c.154C>T
MANE Select: NM_001336
Type: single nucleotide variant
Location: chr20:59006475 (GRCh38)
Gene constraint: LOEUF 1.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.35 · 2 PDB
Residue 52: a disulfide bond

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

Similar variants

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.Ala18Ser Uncertain significance ★ ⚠ same type
CTSZ p.Ala18Val Uncertain significance ★ ⚠ same type
CTSZ p.Ala60Glu Uncertain significance ★ ⚠ same type
CTSZ p.Ala60Val 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-arg52trp (accessed [today's date]).

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