Is CTCF p.Ala669Thr (c.2005G>A) pathogenic?

CTCF p.Ala669Thr (c.2005G>A) is classified Uncertain significance in CTCF (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-04-27). AlphaMissense: ambiguous (0.3692); Ultra-rare (popmax 0.0167%, mid); Associated with CTCF-related disorder.

What condition is associated with CTCF p.Ala669Thr (c.2005G>A)?

CTCF p.Ala669Thr (c.2005G>A) is associated with CTCF-related disorder (ClinVar).

How common is CTCF p.Ala669Thr (c.2005G>A) in the general population?

CTCF p.Ala669Thr (c.2005G>A) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about CTCF p.Ala669Thr (c.2005G>A)?

AlphaMissense predicts ambiguous (score 0.3692) — an in-silico prediction, not a clinical call.

CTCF p.Ala669Thr

c.2005G>A · VCV3351056

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3692 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

CTCF-related disorder

Computational evidence

Protein change
AlphaMissense	0.3692	ambiguous
REVEL	0.283	benign-leaning
SaProt	LLR -5.38	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.84	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 9.9	GERP 2, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 8,396 bp · p 0.23 · regional, not allelic
Overall
CADD	34.0	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 0.0167% Middle Eastern · 1/6,002 alleles

Filtering AF 0.00348% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000496% 8/1,611,698 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	6,002
African / African-American	0.00802%	12,463
European (non-Finnish)	8.48e-05%	1,178,578

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.Ala669Thr
Coding: c.2005G>A
MANE Select: NM_006565
Type: single nucleotide variant
Location: chr16:67637693 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.45 · 21 PDB
Residue 669: 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 disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CTCF p.Arg368His Pathogenic/Likely pathogenic ★★ same condition
CTCF p.Glu187Ter Likely pathogenic ★ same condition
CTCF p.Leu366Phe Likely pathogenic ★ same condition
CTCF p.Met329Val Likely pathogenic ★ same condition
CTCF p.Ala697Thr Conflicting classifications of pathogenicity ★ ⚠ same condition
CTCF p.Cys472Arg Uncertain significance ★ ⚠ same condition
CTCF p.Gly375Glu Uncertain significance ⚠ same condition
CTCF p.Val10Ala 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-ala669thr (accessed [today's date]).

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