Is CTNS p.Asp346= (c.1038C>T) pathogenic?

CTNS p.Asp346= (c.1038C>T) is classified Likely benign in CTNS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-14). Ultra-rare (popmax 0.0936%, eas); Associated with ocular cystinosis.

What condition is associated with CTNS p.Asp346= (c.1038C>T)?

CTNS p.Asp346= (c.1038C>T) is associated with ocular cystinosis, juvenile nephropathic cystinosis, nephropathic cystinosis (ClinVar).

How common is CTNS p.Asp346= (c.1038C>T) in the general population?

CTNS p.Asp346= (c.1038C>T) is ultra-rare (popmax 0.0936%, eas) (gnomAD).

How is Cystinosis inherited?

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

CTNS p.Asp346=

c.1038C>T · rs771450572 · VCV1095045

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0936%, eas)

Conditions

ocular cystinosis

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 -0.84	GERP -3.1
Overall
CADD	1.907	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0936% East Asian · 42/44,888 alleles

Filtering AF 0.0711% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0632%

Overall 0.00458% 74/1,614,250 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0936%	1,069
African / African-American	0.00799%	12,513
South Asian	0.0022%	45,545
European (non-Finnish)	0.00195%	51,307
Remaining individualsnot grpmax-eligible	0.0016%	62,504

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.Asp346=
Coding: c.1038C>T
MANE Select: NM_004937
dbSNP: rs771450572
Type: single nucleotide variant
Location: chr17:3660303 (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 346: an α-helix; a binding site; a UniProt-annotated variant site (in ctns; partial relocation to the cell membrane; abolished cystine transport); a UniProt-annotated variant site (in ctns; atypical; slightly decreased cystine transport; abolished ph-dependent conformational shift)

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

Disease context

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

Also linked: juvenile nephropathic cystinosis nephropathic cystinosis

For Cystinosis (Orphanet):

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

Similar variants

CTNS p.Asp346Asn Uncertain significance ★★ ⚠ same residue
CTNS p.Asp346_Phe349del Conflicting classifications of pathogenicity ★ 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-asp346 (accessed [today's date]).

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