Is CTSE p.Pro321Leu (c.962C>T) pathogenic?

CTSE p.Pro321Leu (c.962C>T) is classified Uncertain significance in CTSE (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely pathogenic (0.6433); Ultra-rare (popmax 0.0165%, mid).

How common is CTSE p.Pro321Leu (c.962C>T) in the general population?

CTSE p.Pro321Leu (c.962C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about CTSE p.Pro321Leu (c.962C>T)?

AlphaMissense predicts likely pathogenic (score 0.6433) — an in-silico prediction, not a clinical call.

CTSE p.Pro321Leu

c.962C>T · rs144940381 · VCV2480287

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6433 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt

Computational evidence

Protein change
AlphaMissense	0.6433	likely pathogenic
SaProt	LLR -12.39	damaging
⇒ AlphaMissense and SaProt both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.1	GERP -0.47, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 14 kb · p 0.083 · regional, not allelic
Overall
CADD	22.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00112% 18/1,613,962 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
African / African-American	0.00267%	37,517
European (non-Finnish)	0.00119%	84,279
South Asian	0.0011%	91,076

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: CTSE
Protein: p.Pro321Leu
Coding: c.962C>T
MANE Select: NM_001910
dbSNP: rs144940381
Type: single nucleotide variant
Location: chr1:206012372 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.31 · 1 PDB
Residue 321: a disulfide bond; the peptidase a1 domain

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

Similar variants

CTSE p.Pro321= Likely benign ★ same residue
CTSE p.Gly80Asp Uncertain significance ★★ ⚠ same type
CTSE p.Ala206Thr Uncertain significance ★ ⚠ same type
CTSE p.Ala259Pro Uncertain significance ★ ⚠ same type
CTSE p.Arg23Ser Uncertain significance ★ ⚠ same type
CTSE p.Arg23Trp Uncertain significance ★ ⚠ same type
CTSE p.Arg28Ser Uncertain significance ★ ⚠ same type
CTSE p.Arg37Gln 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/ctse-p-pro321leu (accessed [today's date]).

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