Is ZRANB2 p.Pro308Ser (c.922C>T) pathogenic?

ZRANB2 p.Pro308Ser (c.922C>T) is classified Uncertain significance in ZRANB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely benign (0.0681); Very rare (popmax 0.00134%, afr).

How common is ZRANB2 p.Pro308Ser (c.922C>T) in the general population?

ZRANB2 p.Pro308Ser (c.922C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ZRANB2 p.Pro308Ser (c.922C>T)?

AlphaMissense predicts likely benign (score 0.0681) — an in-silico prediction, not a clinical call.

ZRANB2 p.Pro308Ser

c.922C>T · VCV3990360

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0681	likely benign
REVEL	0.081	moderately benign-leaning
SaProt	LLR -4.80	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.72 · evaluated, not missing
Constraint at this position
Conservation	phyloP 10	GERP 2.3, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 5,915 bp · p 0.29 · regional, not allelic
Overall
CADD	25.2	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 0.00134% African / African-American · 1/74,780 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,611,210 alleles · very rare exomes 5/1,459,070 · genomes 1/152,140 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,780
European (non-Finnish)	0.000424%	235,820

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: ZRANB2
Protein: p.Pro308Ser
Coding: c.922C>T
MANE Select: NM_203350
Type: single nucleotide variant
Location: chr1:71066783 (GRCh38)
Gene constraint: LOEUF 0.521 · pLI 0.96 (gnomAD)
Structure: AlphaFold pLDDT 56.70 · 3 PDB
Residue 308: the 'disordered' region; the 'required for nuclear targeting' region

Full ZRANB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ZRANB2 p.Arg207Gln Uncertain significance ★ ⚠ same type
ZRANB2 p.Arg212Pro Uncertain significance ★ ⚠ same type
ZRANB2 p.Arg216Cys Uncertain significance ★ ⚠ same type
ZRANB2 p.Arg216His Uncertain significance ★ ⚠ same type
ZRANB2 p.Arg248Leu Uncertain significance ★ ⚠ same type
ZRANB2 p.Arg252His 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/zranb2-p-pro308ser (accessed [today's date]).

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