Is ZBED4 p.Ser91Arg (c.273C>G) pathogenic?

ZBED4 p.Ser91Arg (c.273C>G) is classified Uncertain significance in ZBED4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely pathogenic (0.6409); Very rare (popmax 0.00669%, eas).

How common is ZBED4 p.Ser91Arg (c.273C>G) in the general population?

ZBED4 p.Ser91Arg (c.273C>G) is very rare (popmax 0.00669%, eas) (gnomAD).

What do computational predictors say about ZBED4 p.Ser91Arg (c.273C>G)?

AlphaMissense predicts likely pathogenic (score 0.6409) — an in-silico prediction, not a clinical call.

ZBED4 p.Ser91Arg

c.273C>G · VCV4203562

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6409 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00669%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6409	likely pathogenic
REVEL	0.199	benign-leaning
SaProt	LLR -8.12	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 -0.26	GERP -3.9, phastCons 0.22
Regional constraint	o/e 0.92	unconstrained · MANE · 952 bp · p 0.098 · regional, not allelic
Overall
CADD	15.33	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 0.00669% East Asian · 3/44,872 alleles

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

Overall 0.000248% 4/1,613,308 alleles · very rare exomes 4/1,461,060 · genomes 0/152,248 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00669%	14,957
Remaining individualsnot grpmax-eligible	0.0016%	62,456

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.Ser91Arg
Coding: c.273C>G
MANE Select: NM_014838
Type: single nucleotide variant
Location: chr22:49883935 (GRCh38)
Gene constraint: LOEUF 0.729 · pLI 0.35 (gnomAD)
Structure: AlphaFold pLDDT 67.86

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

Similar variants

ZBED4 p.Ala59= Benign ★★ same type
ZBED4 p.Asn810= Benign ★★ same type
ZBED4 p.Met1150Thr Benign ★★ same type
ZBED4 p.Ser824= Benign ★★ same type
ZBED4 p.Thr575= Benign ★★ same type
ZBED4 p.Ala1051Val Uncertain significance ★ ⚠ same type
ZBED4 p.Ala1060Thr Uncertain significance ★ ⚠ same type
ZBED4 p.Ala1060Val 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/zbed4-p-ser91arg (accessed [today's date]).

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