Is CTNS p.Ile133Met (c.399C>G) pathogenic?

CTNS p.Ile133Met (c.399C>G) is classified Uncertain significance in CTNS (ClinVar, Single submitter, 2 submitters; last evaluated 2022-07-15). AlphaMissense: likely benign (0.1015); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with CTNS p.Ile133Met (c.399C>G)?

CTNS p.Ile133Met (c.399C>G) is associated with Inborn genetic diseases, ocular cystinosis, juvenile nephropathic cystinosis (ClinVar).

How common is CTNS p.Ile133Met (c.399C>G) in the general population?

CTNS p.Ile133Met (c.399C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTNS p.Ile133Met (c.399C>G)?

AlphaMissense predicts likely benign (score 0.1015) — an in-silico prediction, not a clinical call.

CTNS p.Ile133Met

c.399C>G · rs2076100651 · VCV2017562

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1015 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1015	likely benign
REVEL	0.879	moderately pathogenic-leaning
SaProt	LLR -8.99	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	Δ0.20	donor loss, 36 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 1.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	24.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTNS
Protein: p.Ile133Met
Coding: c.399C>G
MANE Select: NM_004937
dbSNP: rs2076100651
Type: single nucleotide variant
Location: chr17:3655290 (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 133: an α-helix; the pq-loop 1 domain; a UniProt-annotated variant site (in ctns; does not affect cystine transport)

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

Also linked: ocular cystinosis juvenile nephropathic cystinosis cystinosis

Similar variants

CTNS c.140+1G>T Pathogenic/Likely pathogenic ★★ same condition
CTNS c.140+2T>C Pathogenic/Likely pathogenic ★★ same condition
CTNS c.141-1G>A Pathogenic/Likely pathogenic ★★ same condition
CTNS c.141-24T>C Pathogenic ★★ same condition
CTNS c.225+3A>T Pathogenic/Likely pathogenic ★★ same condition
CTNS c.225+5G>A Likely pathogenic ★★ same condition
CTNS c.61+2T>C Likely pathogenic ★★ same condition
CTNS c.61+5G>A 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/ctns-p-ile133met (accessed [today's date]).

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