Is CTCFL p.Pro431Leu (c.1292C>T) pathogenic?

CTCFL p.Pro431Leu (c.1292C>T) is classified Uncertain significance in CTCFL (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-11). AlphaMissense: ambiguous (0.437); Ultra-rare (popmax 0.0351%, sas).

How common is CTCFL p.Pro431Leu (c.1292C>T) in the general population?

CTCFL p.Pro431Leu (c.1292C>T) is ultra-rare (popmax 0.0351%, sas) (gnomAD).

What do computational predictors say about CTCFL p.Pro431Leu (c.1292C>T)?

AlphaMissense predicts ambiguous (score 0.437) — an in-silico prediction, not a clinical call.

CTCFL p.Pro431Leu

c.1292C>T · rs568862189 · VCV3078567

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.437 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0351%, sas)

Computational evidence

Protein change
AlphaMissense	0.437	ambiguous
REVEL	0.51	indeterminate
SaProt	LLR -11.78	damaging
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.5, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 11 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	27.5	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 0.0351% South Asian · 32/91,082 alleles

Filtering AF 0.0256% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0222%

Overall 0.00211% 34/1,614,188 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0351%	2,846
Remaining individualsnot grpmax-eligible	0.0032%	31,255

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.Pro431Leu
Coding: c.1292C>T
MANE Select: NM_001386993
dbSNP: rs568862189
Type: single nucleotide variant
Location: chr20:57514630 (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.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-pro431leu (accessed [today's date]).

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