Is CTC1 p.His84fs (c.248_251dup) pathogenic?

CTC1 p.His84fs (c.248251dup) is classified Pathogenic/Likely pathogenic in CTC1 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-07-13). Ultra-rare (popmax 0.0167%, amr); Associated with cerebroretinal microangiopathy with calcifications and cysts 1.

How common is CTC1 p.His84fs (c.248_251dup) in the general population?

CTC1 p.His84fs (c.248_251dup) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

How is Coats plus syndrome inherited?

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

CTC1 p.His84fs

Q: What condition is associated with CTC1 p.His84fs (c.248_251dup)?

CTC1 p.His84fs (c.248_251dup) is associated with cerebroretinal microangiopathy with calcifications and cysts 1, dyskeratosis congenita (ClinVar).

c.248_251dup · rs745467709 · VCV653432

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Conditions

cerebroretinal microangiopathy with calcifications and cysts 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 3 of 23
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.6	GERP -5.2, phastCons 1
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Admixed American · 10/59,990 alleles

Filtering AF 0.009% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00681%

Overall 0.00198% 32/1,613,880 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0167%	5,999
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)	0.00161%	62,101
South Asian	0.0011%	91,064

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.His84fs
Coding: c.248_251dup
MANE Select: NM_025099
dbSNP: rs745467709
Type: Duplication
Location: chr17:8238575 (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 84: 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.Glu125fs Pathogenic/Likely pathogenic ★★ same condition
CTC1 p.Gly398fs Pathogenic/Likely pathogenic ★★ same condition
CTC1 p.His945fs Pathogenic/Likely pathogenic ★★ same condition
CTC1 p.Leu961fs Pathogenic ★★ same condition
CTC1 p.Lys562Ter Pathogenic/Likely pathogenic ★★ same condition
CTC1 p.Pro999_Glu1000insTer Pathogenic/Likely pathogenic ★★ same condition
CTC1 c.2760dup Likely pathogenic ★ same condition
CTC1 p.Ala924fs 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-his84fs (accessed [today's date]).

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