Is CTSC p.Ile453Val (c.1357A>G) pathogenic?

CTSC p.Ile453Val (c.1357A>G) is classified Benign/Likely benign in CTSC (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1065); Common (popmax 12.6%, eas) — too common for a highly-penetrant pathogenic allele; Associated with Papillon-Lefevre disease.

What condition is associated with CTSC p.Ile453Val (c.1357A>G)?

CTSC p.Ile453Val (c.1357A>G) is associated with Papillon-Lefevre disease, Haim-Munk syndrome, periodontitis, aggressive (ClinVar).

How is Papillon-Lefèvre syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTSC p.Ile453Val (c.1357A>G)?

AlphaMissense predicts likely benign (score 0.1065) — an in-silico prediction, not a clinical call.

CTSC p.Ile453Val

Q: How common is CTSC p.Ile453Val (c.1357A>G) in the general population?

CTSC p.Ile453Val (c.1357A>G) is common (popmax 12.6%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1357A>G · rs3888798 · VCV198470

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.1065 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 12.6%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Papillon-Lefevre disease

Computational evidence

Protein change
AlphaMissense	0.1065	likely benign
REVEL	0.358	indeterminate
SaProt	LLR -4.44	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	22.5	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 12.6% East Asian · 5,654/44,876 alleles

Filtering AF 12.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 12.2%

Overall 4.86% 78,475/1,613,916 alleles · common

Ancestry group	Frequency	1 in
East Asiangrpmax	12.6%	8
Finnishnot grpmax-eligible	9.14%	11
South Asian	8.25%	12
Admixed American	8.15%	12
African / African-American	6.83%	15
Remaining individualsnot grpmax-eligible	4.33%	23
European (non-Finnish)	3.93%	25
Middle Eastern	2.69%	37
Amishnot grpmax-eligible	2.41%	41
Ashkenazi Jewishnot grpmax-eligible	0.692%	144

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: CTSC
Protein: p.Ile453Val
Coding: c.1357A>G
MANE Select: NM_001814
dbSNP: rs3888798
Type: single nucleotide variant
Location: chr11:88294041 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 453: a UniProt-annotated variant site (in)

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

Disease context

Papillon-Lefevre disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Haim-Munk syndrome periodontitis, aggressive

For Papillon-Lefèvre syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Worldwide)

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-ile453val (accessed [today's date]).

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