Is SIX3 p.Arg192= (c.576C>T) pathogenic?

SIX3 p.Arg192= (c.576C>T) is classified Benign in SIX3 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-02). Common (popmax 5.04%, afr) — too common for a highly-penetrant pathogenic allele; Associated with schizencephaly.

What condition is associated with SIX3 p.Arg192= (c.576C>T)?

SIX3 p.Arg192= (c.576C>T) is associated with schizencephaly, holoprosencephaly 2 (ClinVar).

How is Schizencephaly inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

SIX3 p.Arg192=

Q: How common is SIX3 p.Arg192= (c.576C>T) in the general population?

SIX3 p.Arg192= (c.576C>T) is common (popmax 5.04%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.576C>T · rs182881 · VCV65500

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 5.04%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

schizencephaly

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 0.22	GERP -2.3, phastCons 0.97
Overall
CADD	13.0	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 5.04% African / African-American · 3,779/75,008 alleles

Filtering AF 4.9% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.85%

Overall 2.12% 34,020/1,601,098 alleles · common exomes 29,832/1,448,814 · genomes 4,188/152,284 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	5.04%	20
Ashkenazi Jewishnot grpmax-eligible	3.05%	33
South Asian	2.34%	43
Remaining individualsnot grpmax-eligible	2.26%	44
Middle Eastern	2.18%	46
European (non-Finnish)	2.04%	49
Admixed American	1.52%	66
Finnishnot grpmax-eligible	1.22%	82
East Asian	0.181%	553

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: SIX3
Protein: p.Arg192=
Coding: c.576C>T
MANE Select: NM_005413
dbSNP: rs182881
Type: single nucleotide variant
Location: chr2:44942680 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38

Full SIX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: holoprosencephaly 2

For Schizencephaly (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

SIX3 p.Ala72Val Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg146Cys Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg201His Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg281Ser Uncertain significance ★★ same condition
SIX3 p.Asp205His Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly244Cys Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly317Ser 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/six3-p-arg192 (accessed [today's date]).

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