Is CTNS p.Cys224Arg (c.670T>C) pathogenic?

CTNS p.Cys224Arg (c.670T>C) is classified Uncertain significance in CTNS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-17). AlphaMissense: ambiguous (0.3624); Very rare (popmax 6.84e-05%); Associated with Inborn genetic diseases.

What condition is associated with CTNS p.Cys224Arg (c.670T>C)?

CTNS p.Cys224Arg (c.670T>C) is associated with Inborn genetic diseases (ClinVar).

How common is CTNS p.Cys224Arg (c.670T>C) in the general population?

CTNS p.Cys224Arg (c.670T>C) is very rare (popmax 6.84e-05%) (gnomAD).

What do computational predictors say about CTNS p.Cys224Arg (c.670T>C)?

AlphaMissense predicts ambiguous (score 0.3624) — an in-silico prediction, not a clinical call.

CTNS p.Cys224Arg

c.670T>C · VCV4616720

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3624 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.84e-05%)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3624	ambiguous
REVEL	0.501	indeterminate
SaProt	LLR -10.24	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 0.34, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.4 · regional, not allelic
Overall
CADD	22.0	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 6.84e-05%

Overall 6.84e-05% 1/1,460,994 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.Cys224Arg
Coding: c.670T>C
MANE Select: NM_004937
Type: single nucleotide variant
Location: chr17:3656784 (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 224: an α-helix

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

Similar variants

CTNS p.Cys224Ter Likely pathogenic ★ same residue
CTNS c.140+2T>C Pathogenic/Likely pathogenic ★★ same condition
CTNS c.61+5G>A Pathogenic/Likely pathogenic ★★ same condition
CTNS c.970+5G>A Pathogenic/Likely pathogenic ★★ same condition
CTNS p.Ala212Val Pathogenic/Likely pathogenic ★★ same condition
CTNS p.Asn323Lys Pathogenic ★★ same condition
CTNS p.Ser139Phe Pathogenic/Likely pathogenic ★★ same condition
CTNS p.Trp182Arg 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-cys224arg (accessed [today's date]).

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