Is ZIC2 p.Ala92= (c.276C>A) pathogenic?

ZIC2 p.Ala92= (c.276C>A) is classified Likely benign in ZIC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-01). Very rare (popmax 0.00272%, amr); Associated with holoprosencephaly 5.

What condition is associated with ZIC2 p.Ala92= (c.276C>A)?

ZIC2 p.Ala92= (c.276C>A) is associated with holoprosencephaly 5 (ClinVar).

How common is ZIC2 p.Ala92= (c.276C>A) in the general population?

ZIC2 p.Ala92= (c.276C>A) is very rare (popmax 0.00272%, amr) (gnomAD).

ZIC2 p.Ala92=

c.276C>A · VCV4761838

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00272%, 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 -4.7	GERP -3.8
Overall
CADD	3.882	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00272% Admixed American · 1/36,738 alleles

Overall 0.000137% 2/1,464,998 alleles · very rare exomes 1/1,313,380 · genomes 1/151,618 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00272%	36,738
Remaining individualsnot grpmax-eligible	0.00179%	55,802

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.Ala92=
Coding: c.276C>A
MANE Select: NM_007129
Type: single nucleotide variant
Location: chr13:99982340 (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-ala92 (accessed [today's date]).

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