Is CTCFL p.Cys259Tyr (c.776G>A) pathogenic?

CTCFL p.Cys259Tyr (c.776G>A) is classified Uncertain significance in CTCFL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-07). AlphaMissense: likely pathogenic (0.99); Absent from gnomAD v4.1.

How common is CTCFL p.Cys259Tyr (c.776G>A) in the general population?

CTCFL p.Cys259Tyr (c.776G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CTCFL p.Cys259Tyr (c.776G>A)?

AlphaMissense predicts likely pathogenic (score 0.99) — an in-silico prediction, not a clinical call.

CTCFL p.Cys259Tyr

c.776G>A · rs777700127 · VCV2558433

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.99 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,048)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.99	likely pathogenic · top 6% in CTCFL
REVEL	0.523	indeterminate
SaProt	LLR -16.11	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.5	GERP 2.7, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 4,856 bp · p 0.1 · 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

No allele count reported in gnomAD v4.1 (AN 1,614,048). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CTCFL
Protein: p.Cys259Tyr
Coding: c.776G>A
MANE Select: NM_001386993
dbSNP: rs777700127
Type: single nucleotide variant
Location: chr20:57519356 (GRCh38)
Gene constraint: LOEUF 0.669 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 55.75

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

Similar variants

CTCFL p.Cys259Ser Uncertain significance ★ ⚠ same residue
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

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-cys259tyr (accessed [today's date]).

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