Is CTC1 p.Arg589Cys (c.1765C>T) pathogenic?

CTC1 p.Arg589Cys (c.1765C>T) is classified Uncertain significance in CTC1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.1064); Very rare (popmax 0.00792%, nfe); Associated with cerebroretinal microangiopathy with calcifications and cysts 1.

How common is CTC1 p.Arg589Cys (c.1765C>T) in the general population?

CTC1 p.Arg589Cys (c.1765C>T) is very rare (popmax 0.00792%, nfe) (gnomAD).

How is Coats plus syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CTC1 p.Arg589Cys (c.1765C>T)?

AlphaMissense predicts likely benign (score 0.1064) — an in-silico prediction, not a clinical call.

CTC1 p.Arg589Cys

Q: What condition is associated with CTC1 p.Arg589Cys (c.1765C>T)?

CTC1 p.Arg589Cys (c.1765C>T) is associated with cerebroretinal microangiopathy with calcifications and cysts 1, dyskeratosis congenita (ClinVar).

c.1765C>T · rs759152295 · VCV856944

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1064 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00792%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebroretinal microangiopathy with calcifications and cysts 1

Computational evidence

Protein change
AlphaMissense	0.1064	likely benign
REVEL	0.25	benign-leaning
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.6	GERP -0.5, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.088 · regional, not allelic
Overall
CADD	28.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00792% European (non-Finnish) · 91/1,148,628 alleles

Filtering AF 0.00657% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00608%

Overall 0.00695% 108/1,555,054 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00995%	10,045
European (non-Finnish)grpmax	0.00792%	12,622
Admixed American	0.00586%	17,063
South Asian	0.00474%	21,098
African / African-American	0.00409%	24,443
East Asian	0.00242%	41,296

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: CTC1
Protein: p.Arg589Cys
Coding: c.1765C>T
MANE Select: NM_025099
dbSNP: rs759152295
Type: single nucleotide variant
Location: chr17:8234508 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.01 · 7 PDB
Residue 589: a β-strand

Full CTC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cerebroretinal microangiopathy with calcifications and cysts 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita

For Coats plus syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: <1 / 1 000 000 (Europe)

Similar variants

CTC1 p.Arg589His Uncertain significance ★★ ⚠ same residue
CTC1 p.Arg589Leu Uncertain significance ★★ ⚠ same residue
CTC1 c.1617+5G>T Pathogenic/Likely pathogenic ★★ same condition
CTC1 c.1818+1G>A Likely pathogenic ★★ same condition
CTC1 c.2386-1G>A Likely pathogenic ★★ same condition
CTC1 c.2758+1G>T Pathogenic/Likely pathogenic ★★ same condition
CTC1 c.3221+1G>A Likely pathogenic ★★ same condition
CTC1 p.Ala227Val 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/ctc1-p-arg589cys (accessed [today's date]).

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