Is CTSC p.Ser6Ala (c.16T>G) pathogenic?

CTSC p.Ser6Ala (c.16T>G) is classified Conflicting classifications of pathogenicity in CTSC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-12-14). AlphaMissense: likely benign (0.0624); Very rare (popmax 0.00404%, nfe); Associated with periodontitis, aggressive.

What condition is associated with CTSC p.Ser6Ala (c.16T>G)?

CTSC p.Ser6Ala (c.16T>G) is associated with periodontitis, aggressive, Papillon-Lefevre disease, Haim-Munk syndrome (ClinVar).

How common is CTSC p.Ser6Ala (c.16T>G) in the general population?

CTSC p.Ser6Ala (c.16T>G) is very rare (popmax 0.00404%, nfe) (gnomAD).

What do computational predictors say about CTSC p.Ser6Ala (c.16T>G)?

AlphaMissense predicts likely benign (score 0.0624) — an in-silico prediction, not a clinical call.

CTSC p.Ser6Ala

c.16T>G · rs750157767 · VCV2258688

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00404%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

periodontitis, aggressive

Computational evidence

Protein change
AlphaMissense	0.0624	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -5.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.63	GERP -2.8
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	0.313	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 0.00404% European (non-Finnish) · 47/1,162,146 alleles

Filtering AF 0.00312% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00279%

Overall 0.00304% 48/1,579,274 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00404%	24,727
Remaining individualsnot grpmax-eligible	0.00163%	61,180

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.Ser6Ala
Coding: c.16T>G
MANE Select: NM_001814
dbSNP: rs750157767
Type: single nucleotide variant
Location: chr11:88337657 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB

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-ser6ala (accessed [today's date]).

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