Is CTNS p.Ile8fs (c.22_23del) pathogenic?

CTNS p.Ile8fs (c.2223del) is classified Likely pathogenic in CTNS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-04). Very rare (popmax 8.48e-05%, nfe); Associated with nephropathic cystinosis.

What condition is associated with CTNS p.Ile8fs (c.22_23del)?

CTNS p.Ile8fs (c.22_23del) is associated with nephropathic cystinosis (ClinVar).

How common is CTNS p.Ile8fs (c.22_23del) in the general population?

CTNS p.Ile8fs (c.22_23del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Cystinosis inherited?

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

CTNS p.Ile8fs

c.22_23del · VCV3775599

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

nephropathic cystinosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 12
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP -0.46, phastCons 0.8
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,908 alleles

Overall 0.000124% 2/1,613,948 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,484
European (non-Finnish)grpmax	8.48e-05%	1,179,908

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile8fs
Coding: c.22_23del
MANE Select: NM_004937
Type: Deletion
Location: chr17:3640227 (GRCh38)
Gene constraint: LOEUF 0.754 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 89.27 · 6 PDB

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

Disease context

nephropathic cystinosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Cystinosis (Orphanet):

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

Similar variants

CTNS p.Ile8Val Uncertain significance ★★ ⚠ same residue
CTNS c.226del Pathogenic/Likely pathogenic ★★ same condition
CTNS c.559_561+24del Pathogenic/Likely pathogenic ★★ same condition
CTNS c.561+1del Pathogenic/Likely pathogenic ★★ same condition
CTNS c.61_61+2del Pathogenic/Likely pathogenic ★★ same condition
CTNS p.Gln108fs Pathogenic ★★ same condition
CTNS p.Gly258fs Pathogenic ★★ same condition
CTNS p.His105fs 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-ile8fs (accessed [today's date]).

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