Is CTC1 p.Val259Met (c.775G>A) pathogenic?

CTC1 p.Val259Met (c.775G>A) is classified Pathogenic/Likely pathogenic in CTC1 (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-08-31). AlphaMissense: ambiguous (0.4079); Very rare (popmax 0.005%, amr); Associated with CTC1-related disorder.

What condition is associated with CTC1 p.Val259Met (c.775G>A)?

CTC1 p.Val259Met (c.775G>A) is associated with CTC1-related disorder, dyskeratosis congenita, cerebroretinal microangiopathy with calcifications and cysts 1 (ClinVar).

How common is CTC1 p.Val259Met (c.775G>A) in the general population?

CTC1 p.Val259Met (c.775G>A) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about CTC1 p.Val259Met (c.775G>A)?

AlphaMissense predicts ambiguous (score 0.4079) — an in-silico prediction, not a clinical call.

CTC1 p.Val259Met

c.775G>A · rs387907080 · VCV30998

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.4079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

CTC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4079	ambiguous
REVEL	0.485	indeterminate
SaProt	LLR -10.09	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 2.3, phastCons 0.99
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.088 · regional, not allelic
Overall
CADD	24.9	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 0.005% Admixed American · 3/59,988 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000616% 9/1,461,880 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,996
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000424%	236,001

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.Val259Met
Coding: c.775G>A
MANE Select: NM_025099
dbSNP: rs387907080
Type: single nucleotide variant
Location: chr17:8237392 (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 259: a UniProt-annotated variant site (in crmcc1)

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

Disease context

CTC1-related disorder

Also linked: dyskeratosis congenita cerebroretinal microangiopathy with calcifications and cysts 1

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-val259met (accessed [today's date]).

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