Is CTNS p.Val344Ile (c.1030G>A) pathogenic?

CTNS p.Val344Ile (c.1030G>A) is classified Uncertain significance in CTNS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-28). AlphaMissense: likely benign (0.0676); Ultra-rare (popmax 0.0395%, sas); Associated with juvenile nephropathic cystinosis.

What condition is associated with CTNS p.Val344Ile (c.1030G>A)?

CTNS p.Val344Ile (c.1030G>A) is associated with juvenile nephropathic cystinosis, ocular cystinosis, nephropathic cystinosis (ClinVar).

How common is CTNS p.Val344Ile (c.1030G>A) in the general population?

CTNS p.Val344Ile (c.1030G>A) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

What do computational predictors say about CTNS p.Val344Ile (c.1030G>A)?

AlphaMissense predicts likely benign (score 0.0676) — an in-silico prediction, not a clinical call.

CTNS p.Val344Ile

c.1030G>A · VCV3581881

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0676 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

juvenile nephropathic cystinosis

Computational evidence

Protein change
AlphaMissense	0.0676	likely benign
REVEL	0.266	benign-leaning
SaProt	LLR -5.90	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 0.067	GERP -0.78, phastCons 0.96
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	6.87	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 0.0395% South Asian · 36/91,088 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.00335% 54/1,614,238 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
Admixed American	0.005%	20,008
Remaining individualsnot grpmax-eligible	0.0048%	20,835
European (non-Finnish)	0.00102%	98,336

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.Val344Ile
Coding: c.1030G>A
MANE Select: NM_004937
Type: single nucleotide variant
Location: chr17:3660295 (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 344: 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

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

Also linked: ocular cystinosis nephropathic cystinosis

Similar variants

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
CTNS c.61+2T>C 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-val344ile (accessed [today's date]).

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