Is CTNS p.Gln189His (c.567G>C) pathogenic?

CTNS p.Gln189His (c.567G>C) is classified Uncertain significance in CTNS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-15). AlphaMissense: likely pathogenic (0.5881); Very rare (popmax 0.000509%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTNS p.Gln189His (c.567G>C)?

CTNS p.Gln189His (c.567G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CTNS p.Gln189His (c.567G>C) in the general population?

CTNS p.Gln189His (c.567G>C) is very rare (popmax 0.000509%, nfe) (gnomAD).

What do computational predictors say about CTNS p.Gln189His (c.567G>C)?

AlphaMissense predicts likely pathogenic (score 0.5881) — an in-silico prediction, not a clinical call.

CTNS p.Gln189His

c.567G>C · VCV4616719

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000509%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5881	likely pathogenic
REVEL	0.8	moderately pathogenic-leaning
SaProt	LLR -11.14	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.22	acceptor loss, 1 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 9.7	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	26.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.000509% European (non-Finnish) · 6/1,179,888 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000411% 6/1,461,560 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: CTNS
Protein: p.Gln189His
Coding: c.567G>C
MANE Select: NM_004937
Type: single nucleotide variant
Location: chr17:3656681 (GRCh38)
Gene constraint: LOEUF 0.754 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.27 · 6 PDB
Residue 189: an α-helix; the pq-loop 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTNS p.Gln189Ter Pathogenic/Likely pathogenic ★★ same residue
CTNS c.140+2T>C Pathogenic/Likely pathogenic ★★ same condition
CTNS c.61+5G>A Pathogenic/Likely pathogenic ★★ same condition
CTNS c.970+5G>A Pathogenic/Likely pathogenic ★★ same condition
CTNS p.Ala212Val Pathogenic/Likely pathogenic ★★ same condition
CTNS p.Asn323Lys Pathogenic ★★ same condition
CTNS p.Ser139Phe Pathogenic/Likely pathogenic ★★ same condition
CTNS p.Trp182Arg 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/ctns-p-gln189his (accessed [today's date]).

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