Is CTNS p.Leu278Pro (c.833T>C) pathogenic?

CTNS p.Leu278Pro (c.833T>C) is classified Uncertain significance in CTNS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-02-12). AlphaMissense: likely pathogenic (0.9444); Ultra-rare (popmax 0.0483%, amr); Associated with ocular cystinosis.

What condition is associated with CTNS p.Leu278Pro (c.833T>C)?

CTNS p.Leu278Pro (c.833T>C) is associated with ocular cystinosis, juvenile nephropathic cystinosis, cystinosis (ClinVar).

How common is CTNS p.Leu278Pro (c.833T>C) in the general population?

CTNS p.Leu278Pro (c.833T>C) is ultra-rare (popmax 0.0483%, 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.Leu278Pro (c.833T>C)?

AlphaMissense predicts likely pathogenic (score 0.9444) — an in-silico prediction, not a clinical call.

CTNS p.Leu278Pro

c.833T>C · rs1314998853 · VCV648616

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9444 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0483%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ocular cystinosis

Computational evidence

Protein change
AlphaMissense	0.9444	likely pathogenic · top 7% in CTNS
REVEL	0.97	strongly pathogenic-leaning
SaProt	LLR -13.92	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.81 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0483% Admixed American · 29/60,004 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0299%

Overall 0.00211% 34/1,611,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0483%	2,069
Remaining individualsnot grpmax-eligible	0.00321%	31,159
East Asian	0.00223%	44,888
European (non-Finnish)	0.00017%	589,890

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.Leu278Pro
Coding: c.833T>C
MANE Select: NM_004937
dbSNP: rs1314998853
Type: single nucleotide variant
Location: chr17:3658156 (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 278: an α-helix; the pq-loop 2 domain

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.Leu278= 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-leu278pro (accessed [today's date]).

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