Is CTSD p.Leu342Pro (c.1025T>C) pathogenic?

CTSD p.Leu342Pro (c.1025T>C) is classified Uncertain significance in CTSD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely pathogenic (0.9623); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTSD p.Leu342Pro (c.1025T>C)?

CTSD p.Leu342Pro (c.1025T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CTSD p.Leu342Pro (c.1025T>C) in the general population?

CTSD p.Leu342Pro (c.1025T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CTSD p.Leu342Pro (c.1025T>C)?

AlphaMissense predicts likely pathogenic (score 0.9623) — an in-silico prediction, not a clinical call.

CTSD p.Leu342Pro

c.1025T>C · VCV4235842

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9623 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9623	likely pathogenic
REVEL	0.593	indeterminate
SaProt	LLR -13.67	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	phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 10 kb · p 0.0029 · regional, not allelic
Overall
CADD	25.2	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 8.48e-05% European (non-Finnish) · 1/1,179,712 alleles

Overall 6.2e-05% 1/1,613,580 alleles · very rare exomes 1/1,461,386 · genomes 0/152,194 · joint denominator

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: CTSD
Protein: p.Leu342Pro
Coding: c.1025T>C
MANE Select: NM_001909
Type: single nucleotide variant
Location: chr11:1753849 (GRCh38)
Gene constraint: LOEUF 0.886 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.69 · 9 PDB
Residue 342: the peptidase a1 domain; a β-strand

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTSD p.Ala116Thr Uncertain significance ★★ ⚠ same condition
CTSD p.Ala18Pro Uncertain significance ★★ ⚠ same condition
CTSD p.Arg205His Uncertain significance ★★ ⚠ same condition
CTSD p.Arg392His Uncertain significance ★★ ⚠ same condition
CTSD p.Asp387Asn Uncertain significance ★★ ⚠ same condition
CTSD p.Gly362Arg Uncertain significance ★★ ⚠ same condition
CTSD p.Gly391Ser Uncertain significance ★★ ⚠ same condition
CTSD p.Ile198Val Uncertain significance ★★ ⚠ same condition

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/ctsd-p-leu342pro (accessed [today's date]).

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