Is CTCF p.Phe416Leu (c.1248T>A) pathogenic?

CTCF p.Phe416Leu (c.1248T>A) is classified Uncertain significance in CTCF (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-28). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1.

How common is CTCF p.Phe416Leu (c.1248T>A) in the general population?

CTCF p.Phe416Leu (c.1248T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTCF p.Phe416Leu (c.1248T>A)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

CTCF p.Phe416Leu

c.1248T>A · rs2142849567 · VCV1309776

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic · top 6% in CTCF
REVEL	0.486	indeterminate
SaProt	LLR -15.06	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 5.1	GERP 1.1, phastCons 1
Regional constraint	o/e 0.24	constrained · MANE · 10 kb · p 3.4e-38 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CTCF
Protein: p.Phe416Leu
Coding: c.1248T>A
MANE Select: NM_006565
dbSNP: rs2142849567
Type: single nucleotide variant
Location: chr16:67621482 (GRCh38)
Gene constraint: LOEUF 0.205 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 59.45 · 21 PDB
Residue 416: a UniProt-annotated variant site (found in an endometrial carcinoma sample; uncertain significance); a β-strand

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

Similar variants

CTCF c.782-1G>A Pathogenic/Likely pathogenic ★★ same type
CTCF c.782-1G>C Pathogenic/Likely pathogenic ★★ same type
CTCF c.782-2A>G Pathogenic/Likely pathogenic ★★ same type
CTCF c.782-2A>T Pathogenic ★★ same type
CTCF p.Arg283His Likely pathogenic ★★ ⚠ same type
CTCF p.Arg342Cys Pathogenic/Likely pathogenic ★★ same type
CTCF p.Arg342His Pathogenic/Likely pathogenic ★★ same type
CTCF p.Arg368Cys Pathogenic ★★ same type

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-phe416leu (accessed [today's date]).

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