Is CTCF p.Pro378Leu (c.1133C>T) pathogenic?

CTCF p.Pro378Leu (c.1133C>T) is classified Pathogenic/Likely pathogenic in CTCF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-09-20). AlphaMissense: likely pathogenic (0.9987); Very rare (popmax 0.000256%, nfe); Associated with Inborn genetic diseases.

What condition is associated with CTCF p.Pro378Leu (c.1133C>T)?

CTCF p.Pro378Leu (c.1133C>T) is associated with Inborn genetic diseases, CTCF-related neurodevelopmental disorder (ClinVar).

How common is CTCF p.Pro378Leu (c.1133C>T) in the general population?

CTCF p.Pro378Leu (c.1133C>T) is very rare (popmax 0.000256%, nfe) (gnomAD).

What do computational predictors say about CTCF p.Pro378Leu (c.1133C>T)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

CTCF p.Pro378Leu

c.1133C>T · rs2142847512 · VCV1325781

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000256%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic ✓ concordant with ClinVar
REVEL	0.526	indeterminate
SaProt	LLR -12.84	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 10 kb · p 3.4e-38 · regional, not allelic
Overall
CADD	32.0	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 0.000256% European (non-Finnish) · 3/1,169,718 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000207% 3/1,448,326 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.Pro378Leu
Coding: c.1133C>T
MANE Select: NM_006565
dbSNP: rs2142847512
Type: single nucleotide variant
Location: chr16:67620743 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.45 · 21 PDB
Residue 378: 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

Also linked: CTCF-related neurodevelopmental disorder

Similar variants

CTCF p.Pro378= Likely benign ★★ 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
CTCF p.Arg342His 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-pro378leu (accessed [today's date]).

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