Is CTNS p.Gln222Arg (c.665A>G) pathogenic?

CTNS p.Gln222Arg (c.665A>G) is classified Likely pathogenic in CTNS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-26). AlphaMissense: likely pathogenic (0.925); Very rare (popmax 0.000424%, nfe); Associated with nephropathic cystinosis.

What condition is associated with CTNS p.Gln222Arg (c.665A>G)?

CTNS p.Gln222Arg (c.665A>G) is associated with nephropathic cystinosis (ClinVar).

How common is CTNS p.Gln222Arg (c.665A>G) in the general population?

CTNS p.Gln222Arg (c.665A>G) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Cystinosis inherited?

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

What do computational predictors say about CTNS p.Gln222Arg (c.665A>G)?

AlphaMissense predicts likely pathogenic (score 0.925) — an in-silico prediction, not a clinical call.

CTNS p.Gln222Arg

c.665A>G · rs1327959008 · VCV2576715

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.925 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

nephropathic cystinosis

Computational evidence

Protein change
AlphaMissense	0.925	likely pathogenic ✓ concordant with ClinVar · top 9% in CTNS
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -13.91	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	24.8	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 0.000424% European (non-Finnish) · 5/1,179,954 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,046 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.Gln222Arg
Coding: c.665A>G
MANE Select: NM_004937
dbSNP: rs1327959008
Type: single nucleotide variant
Location: chr17:3656779 (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 222: an α-helix; a UniProt-annotated variant site (in ctns; partial relocation to the cell membrane; abolished cystine transport)

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.Gln222= Likely benign ★ 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.141-24T>C Pathogenic ★★ same condition
CTNS c.225+3A>T Pathogenic/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-gln222arg (accessed [today's date]).

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