Is SIX3 p.Ala30= (c.90G>T) pathogenic?

SIX3 p.Ala30= (c.90G>T) is classified Benign in SIX3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-02-03). Common (popmax 8.13%, amr) — too common for a highly-penetrant pathogenic allele; Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Ala30= (c.90G>T)?

SIX3 p.Ala30= (c.90G>T) is associated with holoprosencephaly 2 (ClinVar).

SIX3 p.Ala30=

Q: How common is SIX3 p.Ala30= (c.90G>T) in the general population?

SIX3 p.Ala30= (c.90G>T) is common (popmax 8.13%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.90G>T · rs78018362 · VCV65505

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Common

common (popmax 8.13%, amr) — too common for a highly-penetrant pathogenic allele

Conditions

holoprosencephaly 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.1	GERP 0.94, phastCons 1
Overall
CADD	13.99	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.13% Admixed American · 4,868/59,904 alleles

Filtering AF 7.94% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.86%

Overall 1.93% 30,746/1,596,786 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	8.13%	12
Ashkenazi Jewishnot grpmax-eligible	7.56%	13
Middle Eastern	5.98%	17
South Asian	4.56%	22
East Asian	3.93%	25
Remaining individualsnot grpmax-eligible	2.53%	40
European (non-Finnish)	1.25%	80
African / African-American	0.892%	112
Finnishnot grpmax-eligible	0.798%	125
Amishnot grpmax-eligible	0.11%	912

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.Ala30=
Coding: c.90G>T
MANE Select: NM_005413
dbSNP: rs78018362
Type: single nucleotide variant
Location: chr2:44942194 (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

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-ala30 (accessed [today's date]).

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