Is CTSC p.Ala307Thr (c.919G>A) pathogenic?

CTSC p.Ala307Thr (c.919G>A) is classified Uncertain significance in CTSC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-06). AlphaMissense: ambiguous (0.3906); Very rare (popmax 0.000169%, nfe); Associated with Haim-Munk syndrome.

What condition is associated with CTSC p.Ala307Thr (c.919G>A)?

CTSC p.Ala307Thr (c.919G>A) is associated with Haim-Munk syndrome, Papillon-Lefevre disease, periodontitis, aggressive (ClinVar).

How common is CTSC p.Ala307Thr (c.919G>A) in the general population?

CTSC p.Ala307Thr (c.919G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

How is Haim-Munk syndrome inherited?

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

What do computational predictors say about CTSC p.Ala307Thr (c.919G>A)?

AlphaMissense predicts ambiguous (score 0.3906) — an in-silico prediction, not a clinical call.

CTSC p.Ala307Thr

c.919G>A · rs548013321 · VCV943207

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3906 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Haim-Munk syndrome

Computational evidence

Protein change
AlphaMissense	0.3906	ambiguous
REVEL	0.626	indeterminate
SaProt	LLR -5.01	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 44 kb · p 0.26 · regional, not allelic
Overall
CADD	23.4	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 0.000169% European (non-Finnish) · 2/1,179,992 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,826 alleles · very rare

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.Ala307Thr
Coding: c.919G>A
MANE Select: NM_001814
dbSNP: rs548013321
Type: single nucleotide variant
Location: chr11:88294479 (GRCh38)
Gene constraint: LOEUF 1.051 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.64 · 18 PDB
Residue 307: a disulfide bond; an α-helix

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

Disease context

Haim-Munk syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Papillon-Lefevre disease periodontitis, aggressive

For Haim-Munk syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

CTSC p.Ala307= 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-ala307thr (accessed [today's date]).

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