Is CTCFL p.Arg499His (c.1496G>A) pathogenic?

CTCFL p.Arg499His (c.1496G>A) is classified Uncertain significance in CTCFL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-03). AlphaMissense: likely pathogenic (0.6099); Very rare (popmax 0.00668%, eas).

How common is CTCFL p.Arg499His (c.1496G>A) in the general population?

CTCFL p.Arg499His (c.1496G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about CTCFL p.Arg499His (c.1496G>A)?

AlphaMissense predicts likely pathogenic (score 0.6099) — an in-silico prediction, not a clinical call.

CTCFL p.Arg499His

c.1496G>A · VCV4235525

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6099 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6099	likely pathogenic
REVEL	0.261	benign-leaning
SaProt	LLR -5.24	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.7	GERP 2.6, phastCons 0.9
Regional constraint	o/e 0.76	unconstrained · MANE · 11 kb · p 1.2e-05 · regional, not allelic
Overall
CADD	22.3	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 0.00668% East Asian · 3/44,904 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000744% 12/1,613,716 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,968
Remaining individualsnot grpmax-eligible	0.0064%	15,620
Admixed American	0.00167%	59,974
European (non-Finnish)	0.000339%	294,952

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.Arg499His
Coding: c.1496G>A
MANE Select: NM_001386993
Type: single nucleotide variant
Location: chr20:57508784 (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-arg499his (accessed [today's date]).

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