Is ZBED4 p.His463Arg (c.1388A>G) pathogenic?

ZBED4 p.His463Arg (c.1388A>G) is classified Uncertain significance in ZBED4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.18); Ultra-rare (popmax 0.0227%, afr).

How common is ZBED4 p.His463Arg (c.1388A>G) in the general population?

ZBED4 p.His463Arg (c.1388A>G) is ultra-rare (popmax 0.0227%, afr) (gnomAD).

What do computational predictors say about ZBED4 p.His463Arg (c.1388A>G)?

AlphaMissense predicts likely benign (score 0.18) — an in-silico prediction, not a clinical call.

ZBED4 p.His463Arg

c.1388A>G · VCV3983411

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.18 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.18	likely benign
REVEL	0.322	indeterminate
SaProt	LLR -4.42	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 5.2	GERP 1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 922 bp · p 0.12 · regional, not allelic
Overall
CADD	22.2	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 0.0227% African / African-American · 17/74,886 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00124% 20/1,612,252 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0227%	4,405
East Asian	0.00223%	44,886
Remaining individualsnot grpmax-eligible	0.0016%	62,392
European (non-Finnish)	8.48e-05%	1,179,166

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: ZBED4
Protein: p.His463Arg
Coding: c.1388A>G
MANE Select: NM_024105 · reported on NM_014838
Type: single nucleotide variant
Location: chr22:49885050 (GRCh38)

Full ZBED4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/zbed4-p-his463arg (accessed [today's date]).

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