Is CTNS p.Phe336Tyr (c.1007T>A) pathogenic?

CTNS p.Phe336Tyr (c.1007T>A) is classified Uncertain significance in CTNS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-10). AlphaMissense: ambiguous (0.5051); Very rare (popmax 0.000254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTNS p.Phe336Tyr (c.1007T>A)?

CTNS p.Phe336Tyr (c.1007T>A) is associated with Inborn genetic diseases, ocular cystinosis, juvenile nephropathic cystinosis (ClinVar).

How common is CTNS p.Phe336Tyr (c.1007T>A) in the general population?

CTNS p.Phe336Tyr (c.1007T>A) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about CTNS p.Phe336Tyr (c.1007T>A)?

AlphaMissense predicts ambiguous (score 0.5051) — an in-silico prediction, not a clinical call.

CTNS p.Phe336Tyr

c.1007T>A · rs375669198 · VCV1984496

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5051 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5051	ambiguous
REVEL	0.939	strongly pathogenic-leaning
SaProt	LLR -11.83	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
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	25.9	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 0.000254% European (non-Finnish) · 3/1,180,054 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,126 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.Phe336Tyr
Coding: c.1007T>A
MANE Select: NM_004937
dbSNP: rs375669198
Type: single nucleotide variant
Location: chr17:3660272 (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 336: a turn

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

Similar variants

CTNS p.Phe336Leu Uncertain significance ★★ ⚠ same residue
CTNS p.Phe336Ser Uncertain significance ★ ⚠ same residue
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-phe336tyr (accessed [today's date]).

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