Is SIX3 p.Thr210= (c.630G>T) pathogenic?

SIX3 p.Thr210= (c.630G>T) is classified Likely benign in SIX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-04). Very rare (popmax 0.00254%, nfe); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Thr210= (c.630G>T)?

SIX3 p.Thr210= (c.630G>T) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Thr210= (c.630G>T) in the general population?

SIX3 p.Thr210= (c.630G>T) is very rare (popmax 0.00254%, nfe) (gnomAD).

SIX3 p.Thr210=

c.630G>T · rs373300081 · VCV2060133

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Conditions

holoprosencephaly 2

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 1.7	GERP -3.3, phastCons 1
Overall
CADD	11.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00254% European (non-Finnish) · 30/1,179,818 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00156%

Overall 0.00187% 30/1,601,892 alleles · very rare exomes 30/1,449,540 · genomes 0/152,352 · 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.Thr210=
Coding: c.630G>T
MANE Select: NM_005413
dbSNP: rs373300081
Type: single nucleotide variant
Location: chr2:44942734 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 210: a DNA-binding region

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

Disease context

holoprosencephaly 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-thr210 (accessed [today's date]).

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