Is CTSC p.Tyr99Phe (c.296A>T) pathogenic?

CTSC p.Tyr99Phe (c.296A>T) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-31). AlphaMissense: likely benign (0.1476); Very rare (popmax 0.00267%, afr); Associated with Papillon-Lefevre disease.

What condition is associated with CTSC p.Tyr99Phe (c.296A>T)?

CTSC p.Tyr99Phe (c.296A>T) is associated with Papillon-Lefevre disease, Haim-Munk syndrome, periodontitis, aggressive (ClinVar).

How common is CTSC p.Tyr99Phe (c.296A>T) in the general population?

CTSC p.Tyr99Phe (c.296A>T) is very rare (popmax 0.00267%, afr) (gnomAD).

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.Tyr99Phe (c.296A>T)?

AlphaMissense predicts likely benign (score 0.1476) — an in-silico prediction, not a clinical call.

CTSC p.Tyr99Phe

c.296A>T · rs200051475 · VCV1449916

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1476 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Papillon-Lefevre disease

Computational evidence

Protein change
AlphaMissense	0.1476	likely benign
REVEL	0.632	indeterminate
SaProt	LLR -7.63	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 7.9	GERP 1.7, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	24.8	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

Grpmax group 0.00267% African / African-American · 2/74,954 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000992% 16/1,612,962 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,477
Remaining individualsnot grpmax-eligible	0.0016%	62,462
European (non-Finnish)	0.0011%	90,699

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.Tyr99Phe
Coding: c.296A>T
MANE Select: NM_001814
dbSNP: rs200051475
Type: single nucleotide variant
Location: chr11:88334959 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 99: a disulfide bond; a β-strand

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 p.Tyr99His Uncertain significance ★ ⚠ same residue
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

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-tyr99phe (accessed [today's date]).

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