Is CTNS p.Val348Ile (c.1042G>A) pathogenic?

CTNS p.Val348Ile (c.1042G>A) is classified Uncertain significance in CTNS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-01-15). AlphaMissense: likely benign (0.0754); Very rare (popmax 0.00891%, eas); Associated with Inborn genetic diseases.

What condition is associated with CTNS p.Val348Ile (c.1042G>A)?

CTNS p.Val348Ile (c.1042G>A) is associated with Inborn genetic diseases, ocular cystinosis, juvenile nephropathic cystinosis (ClinVar).

How common is CTNS p.Val348Ile (c.1042G>A) in the general population?

CTNS p.Val348Ile (c.1042G>A) is very rare (popmax 0.00891%, eas) (gnomAD).

What do computational predictors say about CTNS p.Val348Ile (c.1042G>A)?

AlphaMissense predicts likely benign (score 0.0754) — an in-silico prediction, not a clinical call.

CTNS p.Val348Ile

c.1042G>A · rs768600706 · VCV2200093

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0754 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00891%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0754	likely benign
REVEL	0.219	benign-leaning
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.59	GERP -3.1, phastCons 0.066
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	7.222	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00891% East Asian · 4/44,904 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00124% 20/1,614,122 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00891%	11,226
Admixed American	0.00667%	15,002
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.000847%	118,005

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.Val348Ile
Coding: c.1042G>A
MANE Select: NM_004937
dbSNP: rs768600706
Type: single nucleotide variant
Location: chr17:3660307 (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 348: 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

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

Also linked: ocular cystinosis juvenile nephropathic cystinosis nephropathic cystinosis

Similar variants

CTNS p.Val348del 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
CTNS c.225+5G>A 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-val348ile (accessed [today's date]).

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