Is CTC1 p.Pro520Ala (c.1558C>G) pathogenic?

CTC1 p.Pro520Ala (c.1558C>G) is classified Uncertain significance in CTC1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-23). AlphaMissense: likely benign (0.0621); Ultra-rare (popmax 0.0117%, amr); Associated with cerebroretinal microangiopathy with calcifications and cysts 1.

How common is CTC1 p.Pro520Ala (c.1558C>G) in the general population?

CTC1 p.Pro520Ala (c.1558C>G) is ultra-rare (popmax 0.0117%, amr) (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.Pro520Ala (c.1558C>G)?

AlphaMissense predicts likely benign (score 0.0621) — an in-silico prediction, not a clinical call.

CTC1 p.Pro520Ala

Q: What condition is associated with CTC1 p.Pro520Ala (c.1558C>G)?

CTC1 p.Pro520Ala (c.1558C>G) is associated with cerebroretinal microangiopathy with calcifications and cysts 1, dyskeratosis congenita (ClinVar).

c.1558C>G · rs371714831 · VCV854129

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0621 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cerebroretinal microangiopathy with calcifications and cysts 1

Computational evidence

Protein change
AlphaMissense	0.0621	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.29	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 0.37	GERP -2.9
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.088 · regional, not allelic
Overall
CADD	11.6	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 0.0117% Admixed American · 7/59,820 alleles

Filtering AF 0.00545% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.000744% 12/1,612,756 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,546
African / African-American	0.00534%	18,721
South Asian	0.0011%	90,868

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.Pro520Ala
Coding: c.1558C>G
MANE Select: NM_025099
dbSNP: rs371714831
Type: single nucleotide variant
Location: chr17:8234808 (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 520: an α-helix

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 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
CTC1 p.Arg108Ter Pathogenic ★★ same condition
CTC1 p.Arg1195Ter Pathogenic/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/ctc1-p-pro520ala (accessed [today's date]).

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