Is CTSZ p.Leu196Pro (c.587T>C) pathogenic?

CTSZ p.Leu196Pro (c.587T>C) is classified Benign/Likely benign in CTSZ (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-01). AlphaMissense: likely pathogenic (0.7285); Rare (popmax 0.843%, nfe).

How common is CTSZ p.Leu196Pro (c.587T>C) in the general population?

CTSZ p.Leu196Pro (c.587T>C) is rare (popmax 0.843%, nfe) (gnomAD).

What do computational predictors say about CTSZ p.Leu196Pro (c.587T>C)?

AlphaMissense predicts likely pathogenic (score 0.7285) — an in-silico prediction, not a clinical call.

CTSZ p.Leu196Pro

c.587T>C · rs199825459 · VCV779289

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7285 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.843%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7285	likely pathogenic
REVEL	0.369	indeterminate
SaProt	LLR -12.10	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 11 kb · p 0.27 · regional, not allelic
Overall
CADD	25.6	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 0.843% European (non-Finnish) · 9,929/1,177,368 alleles

Filtering AF 0.829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.824%

Overall 0.711% 11,440/1,608,464 alleles · rare

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	2.09%	48
European (non-Finnish)grpmax	0.843%	119
Remaining individualsnot grpmax-eligible	0.761%	131
South Asian	0.515%	194
Finnishnot grpmax-eligible	0.359%	278
Admixed American	0.345%	290
African / African-American	0.147%	681
Middle Eastern	0.0828%	1,208
Ashkenazi Jewishnot grpmax-eligible	0.0237%	4,221

Amish 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: CTSZ
Protein: p.Leu196Pro
Coding: c.587T>C
MANE Select: NM_001336
dbSNP: rs199825459
Type: single nucleotide variant
Location: chr20:58997654 (GRCh38)
Gene constraint: LOEUF 1.628 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.35 · 2 PDB
Residue 196: a β-strand

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

Similar variants

CTSZ p.Gly191Arg 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
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-leu196pro (accessed [today's date]).

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