Is CTC1 p.Pro725Arg (c.2174C>G) pathogenic?

CTC1 p.Pro725Arg (c.2174C>G) is classified Conflicting classifications of pathogenicity in CTC1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0872); Ultra-rare (popmax 0.097%, afr); Associated with Inborn genetic diseases.

What condition is associated with CTC1 p.Pro725Arg (c.2174C>G)?

CTC1 p.Pro725Arg (c.2174C>G) is associated with Inborn genetic diseases, dyskeratosis congenita (ClinVar).

How common is CTC1 p.Pro725Arg (c.2174C>G) in the general population?

CTC1 p.Pro725Arg (c.2174C>G) is ultra-rare (popmax 0.097%, afr) (gnomAD).

What do computational predictors say about CTC1 p.Pro725Arg (c.2174C>G)?

AlphaMissense predicts likely benign (score 0.0872) — an in-silico prediction, not a clinical call.

CTC1 p.Pro725Arg

c.2174C>G · rs371046424 · VCV948800

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0872 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.097%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0872	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -6.08	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 3.7	GERP 0.66, phastCons 0.74
Regional constraint	o/e 0.96	unconstrained · MANE · 20 kb · p 0.088 · regional, not allelic
Overall
CADD	14.2	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 0.097% African / African-American · 70/72,130 alleles

Filtering AF 0.0788% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0721%

Overall 0.00664% 102/1,535,430 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.097%	1,030
Admixed American	0.00436%	22,959
Remaining individualsnot grpmax-eligible	0.00339%	29,516
European (non-Finnish)	0.00236%	42,448
Finnishnot grpmax-eligible	0.00165%	60,738

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.Pro725Arg
Coding: c.2174C>G
MANE Select: NM_025099
dbSNP: rs371046424
Type: single nucleotide variant
Location: chr17:8232114 (GRCh38)
Gene constraint: LOEUF 0.776 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 78.01 · 7 PDB

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dyskeratosis congenita

Similar variants

CTC1 p.Pro725= 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.Ala227Val 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-pro725arg (accessed [today's date]).

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