Is CTNS p.Ser39Leu (c.116C>T) pathogenic?

CTNS p.Ser39Leu (c.116C>T) is classified Conflicting classifications of pathogenicity in CTNS (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.0949); Rare (popmax 0.386%, amr); Associated with ocular cystinosis.

What condition is associated with CTNS p.Ser39Leu (c.116C>T)?

CTNS p.Ser39Leu (c.116C>T) is associated with ocular cystinosis, juvenile nephropathic cystinosis, cystinosis (ClinVar).

How common is CTNS p.Ser39Leu (c.116C>T) in the general population?

CTNS p.Ser39Leu (c.116C>T) is rare (popmax 0.386%, amr) (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.Ser39Leu (c.116C>T)?

AlphaMissense predicts likely benign (score 0.0949) — an in-silico prediction, not a clinical call.

CTNS p.Ser39Leu

c.116C>T · rs144751390 · VCV322836

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0949 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.386%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

ocular cystinosis

Computational evidence

Protein change
AlphaMissense	0.0949	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -9.72	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	19.54	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 0.386% Admixed American · 232/60,032 alleles

Filtering AF 0.346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.33%

Overall 0.266% 4,298/1,614,128 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.386%	259
European (non-Finnish)	0.325%	308
Remaining individualsnot grpmax-eligible	0.246%	406
African / African-American	0.0586%	1,706
Middle Eastern	0.0495%	2,021
Finnishnot grpmax-eligible	0.0359%	2,782
Ashkenazi Jewishnot grpmax-eligible	0.0236%	4,230
South Asian	0.00549%	18,218

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.Ser39Leu
Coding: c.116C>T
MANE Select: NM_004937
dbSNP: rs144751390
Type: single nucleotide variant
Location: chr17:3647498 (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 39: a β-strand

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 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.Ser39= 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.141-1G>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-ser39leu (accessed [today's date]).

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