Is SIX3 p.Gln175= (c.525G>A) pathogenic?

SIX3 p.Gln175= (c.525G>A) is classified Benign/Likely benign in SIX3 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-27). Low-frequency (popmax 3.04%, afr); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Gln175= (c.525G>A)?

SIX3 p.Gln175= (c.525G>A) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Gln175= (c.525G>A) in the general population?

SIX3 p.Gln175= (c.525G>A) is low-frequency (popmax 3.04%, afr) (gnomAD).

SIX3 p.Gln175=

c.525G>A · rs116680477 · VCV193311

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 3.04%, afr)

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 6.5	GERP 1, phastCons 1
Overall
CADD	12.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 3.04% African / African-American · 2,282/75,002 alleles

Filtering AF 2.94% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.9%

Overall 0.162% 2,583/1,596,266 alleles · low-frequency exomes 1,277/1,443,926 · genomes 1,306/152,340 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	3.04%	33
Remaining individualsnot grpmax-eligible	0.225%	444
Admixed American	0.178%	562
Middle Eastern	0.033%	3,027
Finnishnot grpmax-eligible	0.0143%	6,987
South Asian	0.00993%	10,071
European (non-Finnish)	0.00314%	31,857

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.Gln175=
Coding: c.525G>A
MANE Select: NM_005413
dbSNP: rs116680477
Type: single nucleotide variant
Location: chr2:44942629 (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-gln175 (accessed [today's date]).

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