Is CTNS p.Phe349Cys (c.1046T>G) pathogenic?

CTNS p.Phe349Cys (c.1046T>G) is classified Uncertain significance in CTNS (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-09-16). AlphaMissense: likely pathogenic (0.9289); Ultra-rare (popmax 0.033%, mid).

How common is CTNS p.Phe349Cys (c.1046T>G) in the general population?

CTNS p.Phe349Cys (c.1046T>G) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about CTNS p.Phe349Cys (c.1046T>G)?

AlphaMissense predicts likely pathogenic (score 0.9289) — an in-silico prediction, not a clinical call.

CTNS p.Phe349Cys

c.1046T>G · rs1567716891 · VCV591338

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9289 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9289	likely pathogenic · top 9% in CTNS
REVEL	0.978	strongly pathogenic-leaning
SaProt	LLR -14.68	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 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	28.6	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 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.000137% 2/1,461,872 alleles · ultra-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.Phe349Cys
Coding: c.1046T>G
MANE Select: NM_004937
dbSNP: rs1567716891
Type: single nucleotide variant
Location: chr17:3660311 (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 349: an α-helix; a UniProt-annotated variant site (in ctns; partial relocation to the cell membrane; abolished cystine transport); a UniProt-annotated variant site (in ctns; abolished cystine transport)

Full CTNS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CTNS p.Phe349Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CTNS c.140+1G>C Likely pathogenic ★★ same type
CTNS c.140+1G>T Pathogenic/Likely pathogenic ★★ same type
CTNS c.140+2T>C Pathogenic/Likely pathogenic ★★ same type
CTNS c.141-1G>A Pathogenic/Likely pathogenic ★★ same type
CTNS c.141-24T>C Pathogenic ★★ same type
CTNS c.225+3A>T Pathogenic/Likely pathogenic ★★ same type
CTNS c.225+5G>A Likely pathogenic ★★ same type

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-phe349cys (accessed [today's date]).

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