Is CTCF p.Gln666His (c.1998G>C) pathogenic?

CTCF p.Gln666His (c.1998G>C) is classified Uncertain significance in CTCF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-04). AlphaMissense: likely benign (0.1908); Very rare (popmax 8.65e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTCF p.Gln666His (c.1998G>C)?

CTCF p.Gln666His (c.1998G>C) is associated with Inborn genetic diseases (ClinVar).

How common is CTCF p.Gln666His (c.1998G>C) in the general population?

CTCF p.Gln666His (c.1998G>C) is very rare (popmax 8.65e-05%, nfe) (gnomAD).

What do computational predictors say about CTCF p.Gln666His (c.1998G>C)?

AlphaMissense predicts likely benign (score 0.1908) — an in-silico prediction, not a clinical call.

CTCF p.Gln666His

c.1998G>C · rs1275809540 · VCV3078564

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1908 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.65e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1908	likely benign
REVEL	0.213	benign-leaning
SaProt	LLR -8.22	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 7.6	GERP 0.97, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 8,396 bp · p 0.23 · regional, not allelic
Overall
CADD	21.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.65e-05% European (non-Finnish) · 1/1,155,766 alleles

Overall 0.000658% 1/152,076 alleles · very rare

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.Gln666His
Coding: c.1998G>C
MANE Select: NM_006565
dbSNP: rs1275809540
Type: single nucleotide variant
Location: chr16:67636850 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.45 · 21 PDB
Residue 666: 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

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

Similar variants

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CTCF p.Arg277Gln Uncertain significance ★★ ⚠ same condition
CTCF p.Cys299Arg Uncertain significance ★★ ⚠ same condition
CTCF p.Gly597Arg Uncertain significance ★★ ⚠ same condition
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CTCF p.Ile511Val Uncertain significance ★★ ⚠ 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-gln666his (accessed [today's date]).

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