Is ZIC2 p.Pro295= (c.885G>A) pathogenic?

ZIC2 p.Pro295= (c.885G>A) is classified Likely benign in ZIC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-01). Ultra-rare (popmax 0.0118%, amr); Associated with holoprosencephaly 5.

What condition is associated with ZIC2 p.Pro295= (c.885G>A)?

ZIC2 p.Pro295= (c.885G>A) is associated with holoprosencephaly 5 (ClinVar).

How common is ZIC2 p.Pro295= (c.885G>A) in the general population?

ZIC2 p.Pro295= (c.885G>A) is ultra-rare (popmax 0.0118%, amr) (gnomAD).

ZIC2 p.Pro295=

c.885G>A · rs779344309 · VCV1665567

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0118%, amr)

Conditions

holoprosencephaly 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -8.5	GERP -4.4
Overall
CADD	6.691	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0118% Admixed American · 7/59,434 alleles

Filtering AF 0.00548% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00383%

Overall 0.00361% 58/1,608,094 alleles · ultra-rare exomes 50/1,461,784 · genomes 8/146,310 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0118%	8,491
Remaining individualsnot grpmax-eligible	0.00962%	10,391
European (non-Finnish)	0.00365%	27,399
African / African-American	0.00275%	36,424

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: ZIC2
Protein: p.Pro295=
Coding: c.885G>A
MANE Select: NM_007129
dbSNP: rs779344309
Type: single nucleotide variant
Location: chr13:99982949 (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

holoprosencephaly 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ZIC2 p.Ala228Gly Uncertain significance ★★ ⚠ same condition
ZIC2 p.Ala26Gly Uncertain significance ★★ ⚠ same condition
ZIC2 p.Arg180Cys Uncertain significance ★★ ⚠ same condition
ZIC2 p.Arg346Leu Uncertain significance ★★ ⚠ same condition
ZIC2 p.Glu305Val Uncertain significance ★★ ⚠ same condition
ZIC2 p.Gly155Ser Uncertain significance ★★ ⚠ same condition
ZIC2 p.Gly478Arg Uncertain significance ★★ ⚠ same condition
ZIC2 p.Gly481Val 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-pro295 (accessed [today's date]).

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