Is CTCFL p.Lys249Arg (c.746A>G) pathogenic?

CTCFL p.Lys249Arg (c.746A>G) is classified Uncertain significance in CTCFL (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-27). AlphaMissense: likely benign (0.0933); Rare (popmax 0.115%, mid).

How common is CTCFL p.Lys249Arg (c.746A>G) in the general population?

CTCFL p.Lys249Arg (c.746A>G) is rare (popmax 0.115%, mid) (gnomAD).

What do computational predictors say about CTCFL p.Lys249Arg (c.746A>G)?

AlphaMissense predicts likely benign (score 0.0933) — an in-silico prediction, not a clinical call.

CTCFL p.Lys249Arg

c.746A>G · rs192001621 · VCV3078581

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0933 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.115%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0933	likely benign
REVEL	0.025	moderately benign-leaning
SaProt	LLR -6.43	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 0.71	GERP -0.035
Regional constraint	o/e 1.09	unconstrained · MANE · 4,856 bp · p 0.1 · regional, not allelic
Overall
CADD	12.05	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 0.115% Middle Eastern · 7/6,062 alleles

Filtering AF 0.0542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0478%

Overall 0.00923% 149/1,613,482 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.115%	866
African / African-American	0.068%	1,471
Remaining individualsnot grpmax-eligible	0.0256%	3,905
Admixed American	0.0233%	4,284
European (non-Finnish)	0.00517%	19,340

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: CTCFL
Protein: p.Lys249Arg
Coding: c.746A>G
MANE Select: NM_001386993
dbSNP: rs192001621
Type: single nucleotide variant
Location: chr20:57523076 (GRCh38)
Gene constraint: LOEUF 0.669 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.75
Residue 249: the 'disordered' region

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

Similar variants

CTCFL p.Ser172= Benign ★★ same type
CTCFL p.Val652Met Benign ★★ same type
CTCFL p.Ala155Ser Uncertain significance ★ ⚠ same type
CTCFL p.Ala155Thr Uncertain significance ★ ⚠ same type
CTCFL p.Ala253Thr Uncertain significance ★ ⚠ same type
CTCFL p.Ala321Thr Uncertain significance ★ ⚠ same type
CTCFL p.Ala434Thr Uncertain significance ★ ⚠ same type
CTCFL p.Ala438Thr Uncertain significance ★ ⚠ 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/ctcfl-p-lys249arg (accessed [today's date]).

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