Is ZBED2 p.Pro65Arg (c.194C>G) pathogenic?

ZBED2 p.Pro65Arg (c.194C>G) is classified Uncertain significance in ZBED2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-05). AlphaMissense: ambiguous (0.4086); Very rare (popmax 0.00446%, eas).

How common is ZBED2 p.Pro65Arg (c.194C>G) in the general population?

ZBED2 p.Pro65Arg (c.194C>G) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about ZBED2 p.Pro65Arg (c.194C>G)?

AlphaMissense predicts ambiguous (score 0.4086) — an in-silico prediction, not a clinical call.

ZBED2 p.Pro65Arg

c.194C>G · VCV3471978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Computational evidence

Protein change
AlphaMissense	0.4086	ambiguous
REVEL	0.321	indeterminate
SaProt	LLR -8.46	tolerated
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 6.3	GERP 1.6, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 653 bp · p 0.81 · regional, not allelic
Overall
CADD	23.6	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 0.00446% East Asian · 2/44,874 alleles

Filtering AF 0.000739% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.000137% 2/1,461,866 alleles · very rare

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: ZBED2
Protein: p.Pro65Arg
Coding: c.194C>G
MANE Select: NM_005816 · reported on NM_024508
Type: single nucleotide variant
Location: chr3:111594008 (GRCh38)

Full ZBED2 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/zbed2-p-pro65arg (accessed [today's date]).

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