Is SIX3 p.Arg262= (c.786C>A) pathogenic?

SIX3 p.Arg262= (c.786C>A) is classified Conflicting classifications of pathogenicity in SIX3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2021-08-12). Very rare (popmax 0.00398%, nfe); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Arg262= (c.786C>A)?

SIX3 p.Arg262= (c.786C>A) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Arg262= (c.786C>A) in the general population?

SIX3 p.Arg262= (c.786C>A) is very rare (popmax 0.00398%, nfe) (gnomAD).

SIX3 p.Arg262=

c.786C>A · rs778895549 · VCV498484

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00398%, nfe)

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 -0.31	GERP -3.9, phastCons 0.14
Overall
CADD	11.42	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00398% European (non-Finnish) · 47/1,179,790 alleles

Filtering AF 0.00307% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00275%

Overall 0.003% 48/1,598,344 alleles · very rare exomes 46/1,446,148 · genomes 2/152,196 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00398%	25,102
Remaining individualsnot grpmax-eligible	0.0016%	62,354

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.Arg262=
Coding: c.786C>A
MANE Select: NM_005413
dbSNP: rs778895549
Type: single nucleotide variant
Location: chr2:44942890 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 262: a DNA-binding region; a UniProt-annotated variant site (in hpe2); the 'disordered' 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.Arg262His Uncertain significance ★ ⚠ same residue
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

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-arg262 (accessed [today's date]).

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