Is SIX3 p.Ser70Pro (c.208T>C) pathogenic?

SIX3 p.Ser70Pro (c.208T>C) is classified Uncertain significance in SIX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2016-01-01). AlphaMissense: likely benign (0.0974); Very rare (popmax 0.000682%, nfe); Associated with schizencephaly.

What condition is associated with SIX3 p.Ser70Pro (c.208T>C)?

SIX3 p.Ser70Pro (c.208T>C) is associated with schizencephaly (ClinVar).

How common is SIX3 p.Ser70Pro (c.208T>C) in the general population?

SIX3 p.Ser70Pro (c.208T>C) is very rare (popmax 0.000682%, 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.Ser70Pro (c.208T>C)?

AlphaMissense predicts likely benign (score 0.0974) — an in-silico prediction, not a clinical call.

SIX3 p.Ser70Pro

c.208T>C · rs1314811261 · VCV931003

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0974 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000682%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

schizencephaly

Computational evidence

Protein change
AlphaMissense	0.0974	likely benign
REVEL	0.24	benign-leaning
SaProt	LLR -6.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP -3, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 230 bp · p 0.3 · regional, not allelic
Overall
CADD	23.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000682% European (non-Finnish) · 8/1,173,090 alleles

Filtering AF 0.000293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000505% 8/1,584,544 alleles · very rare exomes 7/1,433,674 · genomes 1/150,870 · joint denominator

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.Ser70Pro
Coding: c.208T>C
MANE Select: NM_005413
dbSNP: rs1314811261
Type: single nucleotide variant
Location: chr2:44942312 (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

For Schizencephaly (Orphanet):

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

Similar variants

SIX3 p.Ser70Cys Uncertain significance ★★ ⚠ same residue
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.Ala167Ser Uncertain significance ★ ⚠ same condition
SIX3 p.Arg260Cys Uncertain significance ★ ⚠ same condition
SIX3 p.Asn36Asp 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-ser70pro (accessed [today's date]).

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