Is ZIC2 p.Pro71= (c.213G>A) pathogenic?

ZIC2 p.Pro71= (c.213G>A) is classified Benign in ZIC2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-15). Low-frequency (popmax 1.07%, afr); Associated with holoprosencephaly 5.

What condition is associated with ZIC2 p.Pro71= (c.213G>A)?

ZIC2 p.Pro71= (c.213G>A) is associated with holoprosencephaly 5 (ClinVar).

How common is ZIC2 p.Pro71= (c.213G>A) in the general population?

ZIC2 p.Pro71= (c.213G>A) is low-frequency (popmax 1.07%, afr) (gnomAD).

ZIC2 p.Pro71=

c.213G>A · rs189469383 · VCV260131

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.07%, afr)

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 -6.4	GERP -3.4
Overall
CADD	1.675	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.07% African / African-American · 738/68,748 alleles

Filtering AF 1.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.984%

Overall 0.0598% 894/1,495,512 alleles · low-frequency exomes 431/1,343,930 · genomes 463/151,582 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.07%	93
Admixed American	0.114%	878
Remaining individualsnot grpmax-eligible	0.0957%	1,045
Middle Eastern	0.0421%	2,376
European (non-Finnish)	0.0039%	25,611
Ashkenazi Jewishnot grpmax-eligible	0.0037%	27,018
South Asian	0.00252%	39,729

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.Pro71=
Coding: c.213G>A
MANE Select: NM_007129
dbSNP: rs189469383
Type: single nucleotide variant
Location: chr13:99982277 (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.Pro71_Ser79del Uncertain significance ★ same residue
ZIC2 p.Pro71Ser Uncertain significance ★ ⚠ same residue
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

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-pro71 (accessed [today's date]).

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