Is CTNS p.Arg228= (c.684C>T) pathogenic?

CTNS p.Arg228= (c.684C>T) is classified Likely benign in CTNS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-05). Ultra-rare (popmax 0.0224%, mid); Associated with Inborn genetic diseases.

What condition is associated with CTNS p.Arg228= (c.684C>T)?

CTNS p.Arg228= (c.684C>T) is associated with Inborn genetic diseases, ocular cystinosis, juvenile nephropathic cystinosis (ClinVar).

How common is CTNS p.Arg228= (c.684C>T) in the general population?

CTNS p.Arg228= (c.684C>T) is ultra-rare (popmax 0.0224%, mid) (gnomAD).

CTNS p.Arg228=

c.684C>T · rs762346133 · VCV740597

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0224%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.22	GERP -3.4, phastCons 0.31
Overall
CADD	5.489	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0224% Middle Eastern · 1/4,474 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.0111% 178/1,608,998 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0224%	4,474
African / African-American	0.0134%	7,487
European (non-Finnish)	0.0133%	7,515
Remaining individualsnot grpmax-eligible	0.00803%	12,453
Admixed American	0.005%	20,003
Finnishnot grpmax-eligible	0.00164%	61,094
South Asian	0.0011%	91,000

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.Arg228=
Coding: c.684C>T
MANE Select: NM_004937
dbSNP: rs762346133
Type: single nucleotide variant
Location: chr17:3658007 (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

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

Also linked: ocular cystinosis juvenile nephropathic cystinosis cystinosis nephropathic cystinosis

Similar variants

CTNS p.Arg228Cys Uncertain significance ★★ ⚠ same residue
CTNS p.Arg228Leu Uncertain significance ★ ⚠ same residue
CTNS c.140+1G>C Likely pathogenic ★★ same condition
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

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-arg228 (accessed [today's date]).

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