Is CTCF p.Arg654= (c.1962A>C) pathogenic?

CTCF p.Arg654= (c.1962A>C) is classified Likely benign in CTCF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2021-09-21). Very rare (popmax 0.00172%, amr); Associated with CTCF-related neurodevelopmental disorder.

What condition is associated with CTCF p.Arg654= (c.1962A>C)?

CTCF p.Arg654= (c.1962A>C) is associated with CTCF-related neurodevelopmental disorder (ClinVar).

How common is CTCF p.Arg654= (c.1962A>C) in the general population?

CTCF p.Arg654= (c.1962A>C) is very rare (popmax 0.00172%, amr) (gnomAD).

How is CTCF-related neurodevelopmental disorder inherited?

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

CTCF p.Arg654=

c.1962A>C · rs772451262 · VCV792812

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00172%, amr)

Conditions

CTCF-related neurodevelopmental disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.25	GERP -4.1, phastCons 0.82
Overall
CADD	7.728	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00172% Admixed American · 1/58,018 alleles

Overall 0.000125% 2/1,597,074 alleles · very rare exomes 1/1,445,262 · genomes 1/151,812 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00172%	58,018
Remaining individualsnot grpmax-eligible	0.00162%	61,804

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.Arg654=
Coding: c.1962A>C
MANE Select: NM_006565
dbSNP: rs772451262
Type: single nucleotide variant
Location: chr16:67636814 (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.Arg654Ter Likely pathogenic ★ 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-arg654 (accessed [today's date]).

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