Is CTC1 p.Pro9Ser (c.25C>T) pathogenic?

CTC1 p.Pro9Ser (c.25C>T) is classified Uncertain significance in CTC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-24). AlphaMissense: likely benign (0.0614); Very rare (popmax 0.00441%, sas); Associated with cerebroretinal microangiopathy with calcifications and cysts 1.

How common is CTC1 p.Pro9Ser (c.25C>T) in the general population?

CTC1 p.Pro9Ser (c.25C>T) is very rare (popmax 0.00441%, sas) (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.Pro9Ser (c.25C>T)?

AlphaMissense predicts likely benign (score 0.0614) — an in-silico prediction, not a clinical call.

CTC1 p.Pro9Ser

Q: What condition is associated with CTC1 p.Pro9Ser (c.25C>T)?

CTC1 p.Pro9Ser (c.25C>T) is associated with cerebroretinal microangiopathy with calcifications and cysts 1, dyskeratosis congenita (ClinVar).

c.25C>T · rs1034774367 · VCV581122

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0614 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebroretinal microangiopathy with calcifications and cysts 1

Computational evidence

Protein change
AlphaMissense	0.0614	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -4.85	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -1.9	GERP -4.4
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.088 · regional, not allelic
Overall
CADD	0.01	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 0.00441% South Asian · 4/90,692 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000894%

Overall 0.000807% 13/1,609,918 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00441%	22,673
Remaining individualsnot grpmax-eligible	0.00322%	31,076
African / African-American	0.00134%	74,782
European (non-Finnish)	0.000509%	196,373

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.Pro9Ser
Coding: c.25C>T
MANE Select: NM_012393 · reported on NM_025099
dbSNP: rs1034774367
Type: single nucleotide variant
Location: chr17:8248012 (GRCh38)

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)

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-pro9ser (accessed [today's date]).

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