Is SIX3 p.Ala167Ser (c.499G>T) pathogenic?

SIX3 p.Ala167Ser (c.499G>T) is classified Uncertain significance in SIX3 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-05-04). AlphaMissense: ambiguous (0.3575); Very rare (popmax 0.00153%, nfe); Associated with schizencephaly.

What condition is associated with SIX3 p.Ala167Ser (c.499G>T)?

SIX3 p.Ala167Ser (c.499G>T) is associated with schizencephaly (ClinVar).

How common is SIX3 p.Ala167Ser (c.499G>T) in the general population?

SIX3 p.Ala167Ser (c.499G>T) is very rare (popmax 0.00153%, nfe) (gnomAD).

How is Schizencephaly inherited?

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

What do computational predictors say about SIX3 p.Ala167Ser (c.499G>T)?

AlphaMissense predicts ambiguous (score 0.3575) — an in-silico prediction, not a clinical call.

SIX3 p.Ala167Ser

c.499G>T · rs387906868 · VCV30382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3575 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

schizencephaly

Computational evidence

Protein change
AlphaMissense	0.3575	ambiguous
REVEL	0.739	pathogenic-leaning
SaProt	LLR -9.72	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 435 bp · p 5.9e-10 · regional, not allelic
Overall
CADD	32.0	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

Grpmax group 0.00153% European (non-Finnish) · 18/1,179,448 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00113% 18/1,598,012 alleles · very rare

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.Ala167Ser
Coding: c.499G>T
MANE Select: NM_005413
dbSNP: rs387906868
Type: single nucleotide variant
Location: chr2:44942603 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 167: a UniProt-annotated variant site (in schzc)

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

For Schizencephaly (Orphanet):

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

Similar variants

SIX3 p.Gly43Cys Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly69Asp Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg192= Benign ★★ same condition
SIX3 p.Gly37Cys Benign/Likely benign ★★ ⚠ same condition
SIX3 p.Arg260Cys Uncertain significance ★ ⚠ same condition
SIX3 p.Asn36Asp Uncertain significance ★ ⚠ same condition
SIX3 p.Ser70Pro Uncertain significance ★ ⚠ same condition
SIX3 p.Glu129Ter Pathogenic 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-ala167ser (accessed [today's date]).

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