Is CTSC p.Val43Leu (c.127G>T) pathogenic?

CTSC p.Val43Leu (c.127G>T) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-28). AlphaMissense: likely benign (0.2632); Absent from gnomAD v4.1; Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Val43Leu (c.127G>T)?

CTSC p.Val43Leu (c.127G>T) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Val43Leu (c.127G>T) in the general population?

CTSC p.Val43Leu (c.127G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTSC p.Val43Leu (c.127G>T)?

AlphaMissense predicts likely benign (score 0.2632) — an in-silico prediction, not a clinical call.

CTSC p.Val43Leu

c.127G>T · rs1350491977 · VCV1994118

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2632 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

periodontitis, aggressive

Computational evidence

Protein change
AlphaMissense	0.2632	likely benign
REVEL	0.521	indeterminate
SaProt	LLR -5.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	Δ0.50	donor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.4	GERP 1.4, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	25.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTSC
Protein: p.Val43Leu
Coding: c.127G>T
MANE Select: NM_001814
dbSNP: rs1350491977
Type: single nucleotide variant
Location: chr11:88337546 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 43: a disulfide bond; a β-strand

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

Disease context

periodontitis, aggressive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Papillon-Lefevre disease Haim-Munk syndrome

Similar variants

CTSC c.319-1G>A Pathogenic ★★ same condition
CTSC c.757+1G>T Likely pathogenic ★★ same condition
CTSC c.-55C>A Pathogenic ★★ same condition
CTSC p.Arg210Ter Pathogenic ★★ same condition
CTSC p.Arg250Ter Pathogenic/Likely pathogenic ★★ same condition
CTSC p.Arg272His Pathogenic/Likely pathogenic ★★ ⚠ same condition
CTSC p.Arg272Pro Pathogenic/Likely pathogenic ★★ same condition
CTSC p.Arg339Cys Pathogenic/Likely pathogenic ★★ ⚠ 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/ctsc-p-val43leu (accessed [today's date]).

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