Is ZIC2 p.Arg346Pro (c.1037G>C) pathogenic?

ZIC2 p.Arg346Pro (c.1037G>C) is classified Likely pathogenic in ZIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-09). AlphaMissense: likely pathogenic (0.9994); Absent from gnomAD v4.1; Associated with ZIC2-related disorder.

What condition is associated with ZIC2 p.Arg346Pro (c.1037G>C)?

ZIC2 p.Arg346Pro (c.1037G>C) is associated with ZIC2-related disorder (ClinVar).

How common is ZIC2 p.Arg346Pro (c.1037G>C) in the general population?

ZIC2 p.Arg346Pro (c.1037G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ZIC2 p.Arg346Pro (c.1037G>C)?

AlphaMissense predicts likely pathogenic (score 0.9994) — an in-silico prediction, not a clinical call.

ZIC2 p.Arg346Pro

c.1037G>C · VCV4920317

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9994 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

ZIC2-related disorder

Computational evidence

Protein change
AlphaMissense	0.9994	likely pathogenic ✓ concordant with ClinVar · top 2% in ZIC2
REVEL	0.943	strongly pathogenic-leaning
SaProt	LLR -12.31	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 10	GERP 2.1, phastCons 1
Regional constraint	o/e 0.31	constrained · MANE · 2,040 bp · p 1.4e-12 · regional, not allelic
Overall
CADD	34.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: ZIC2
Protein: p.Arg346Pro
Coding: c.1037G>C
MANE Select: NM_007129
Type: single nucleotide variant
Location: chr13:99983101 (GRCh38)
Gene constraint: LOEUF 0.52 · pLI 0.96 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 51.36

Full ZIC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

ZIC2-related disorder

Similar variants

ZIC2 p.Arg346Leu Uncertain significance ★★ ⚠ same residue
ZIC2 p.Arg346Cys Uncertain significance ★ ⚠ same residue
ZIC2 p.Arg325His Likely pathogenic ★ same condition
ZIC2 p.Cys251Ter Likely pathogenic ★ same condition
ZIC2 p.His323Tyr Likely pathogenic ★ same condition
ZIC2 p.His415Arg Likely pathogenic ★ same condition
ZIC2 p.Ala31Asp Uncertain significance ★ ⚠ same condition
ZIC2 p.Asn274His Uncertain significance ★ ⚠ same condition

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/zic2-p-arg346pro (accessed [today's date]).

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