Is CTC1 p.Ala227Val (c.680C>T) pathogenic?

CTC1 p.Ala227Val (c.680C>T) is classified Pathogenic in CTC1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-17). AlphaMissense: ambiguous (0.4638); Very rare (popmax 8.47e-05%, nfe); Associated with CTC1-related disorder.

What condition is associated with CTC1 p.Ala227Val (c.680C>T)?

CTC1 p.Ala227Val (c.680C>T) is associated with CTC1-related disorder, dyskeratosis congenita, cerebroretinal microangiopathy with calcifications and cysts 1 (ClinVar).

How common is CTC1 p.Ala227Val (c.680C>T) in the general population?

CTC1 p.Ala227Val (c.680C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about CTC1 p.Ala227Val (c.680C>T)?

AlphaMissense predicts ambiguous (score 0.4638) — an in-silico prediction, not a clinical call.

CTC1 p.Ala227Val

c.680C>T · rs199473673 · VCV31004

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4638 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

CTC1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4638	ambiguous
REVEL	0.562	indeterminate
SaProt	LLR -8.82	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.088 · regional, not allelic
Overall
CADD	23.6	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 8.47e-05% European (non-Finnish) · 1/1,179,946 alleles

Overall 0.00496% 80/1,613,810 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.123%	810
European (non-Finnish)grpmax	8.47e-05%	1,179,947

Finnish 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.Ala227Val
Coding: c.680C>T
MANE Select: NM_025099
dbSNP: rs199473673
Type: single nucleotide variant
Location: chr17:8237487 (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 227: 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 p.Ala227Ser Uncertain significance ★ same residue
CTC1 p.Ala227= Likely benign ★ 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.Arg108Ter 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-ala227val (accessed [today's date]).

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