Is CTCF p.Arg654Ter (c.1960C>T) pathogenic?

CTCF p.Arg654Ter (c.1960C>T) is classified Likely pathogenic in CTCF (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-21). Very rare (popmax 0.00229%, eas); Associated with CTCF-related neurodevelopmental disorder.

What condition is associated with CTCF p.Arg654Ter (c.1960C>T)?

CTCF p.Arg654Ter (c.1960C>T) is associated with CTCF-related neurodevelopmental disorder (ClinVar).

How common is CTCF p.Arg654Ter (c.1960C>T) in the general population?

CTCF p.Arg654Ter (c.1960C>T) is very rare (popmax 0.00229%, eas) (gnomAD).

How is CTCF-related neurodevelopmental disorder inherited?

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

CTCF p.Arg654Ter

c.1960C>T · rs2142887156 · VCV1325773

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00229%, eas)

Conditions

CTCF-related neurodevelopmental disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon within the last 50 nt of the penultimate exon (11 of 12, 39 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -0.18, phastCons 1
Overall
CADD	39.0	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 0.00229% East Asian · 1/43,706 alleles

Overall 0.000125% 2/1,597,120 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00229%	43,706
European (non-Finnish)	8.54e-05%	1,171,358

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: CTCF
Protein: p.Arg654Ter
Coding: c.1960C>T
MANE Select: NM_006565
dbSNP: rs2142887156
Type: single nucleotide variant
Location: chr16:67636812 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.45 · 21 PDB
Residue 654: the 'disordered' region; a UniProt-annotated variant site (found in an endometrial carcinoma sample; uncertain significance)

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

Disease context

CTCF-related neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For CTCF-related neurodevelopmental disorder (Orphanet):

Inheritance: Autosomal dominant
Onset: Antenatal, Childhood, Infancy, Neonatal

Similar variants

CTCF p.Arg654= Likely benign ★★ same residue
CTCF p.Arg654Gln Uncertain significance ★ ⚠ same residue
CTCF c.782-1G>A Pathogenic/Likely pathogenic ★★ same condition
CTCF c.782-1G>C Pathogenic/Likely pathogenic ★★ same condition
CTCF c.782-2A>G Pathogenic/Likely pathogenic ★★ same condition
CTCF c.782-2A>T Pathogenic ★★ same condition
CTCF p.Arg283His Likely pathogenic ★★ same condition
CTCF p.Arg342Cys 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/ctcf-p-arg654ter (accessed [today's date]).

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