Is CTNS p.Ser141Phe (c.422C>T) pathogenic?

CTNS p.Ser141Phe (c.422C>T) is classified Pathogenic/Likely pathogenic in CTNS (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-05-16). AlphaMissense: likely pathogenic (0.969); Very rare (popmax 0.0022%, sas); Associated with ocular cystinosis.

What condition is associated with CTNS p.Ser141Phe (c.422C>T)?

CTNS p.Ser141Phe (c.422C>T) is associated with ocular cystinosis, juvenile nephropathic cystinosis, cystinosis (ClinVar).

How common is CTNS p.Ser141Phe (c.422C>T) in the general population?

CTNS p.Ser141Phe (c.422C>T) is very rare (popmax 0.0022%, sas) (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.Ser141Phe (c.422C>T)?

AlphaMissense predicts likely pathogenic (score 0.969) — an in-silico prediction, not a clinical call.

CTNS p.Ser141Phe

c.422C>T · rs1436441738 · VCV651886

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.969 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ocular cystinosis

Computational evidence

Protein change
AlphaMissense	0.969	likely pathogenic ✓ concordant with ClinVar · top 4% in CTNS
REVEL	0.942	strongly pathogenic-leaning
SaProt	LLR -14.22	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	33.0	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 0.0022% South Asian · 2/91,080 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000137% 2/1,461,866 alleles · very rare

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.Ser141Phe
Coding: c.422C>T
MANE Select: NM_004937
dbSNP: rs1436441738
Type: single nucleotide variant
Location: chr17:3655313 (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 141: a turn; the pq-loop 1 domain; a UniProt-annotated variant site (in ctns; abolished cystine transport)

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 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-ser141phe (accessed [today's date]).

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