Is SIX1 p.Arg110= (c.330G>A) pathogenic?

SIX1 p.Arg110= (c.330G>A) is classified Conflicting classifications of pathogenicity in SIX1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-17). Rare (popmax 0.234%, afr); Associated with branchiootic syndrome 3.

What condition is associated with SIX1 p.Arg110= (c.330G>A)?

SIX1 p.Arg110= (c.330G>A) is associated with branchiootic syndrome 3, autosomal dominant nonsyndromic hearing loss 23 (ClinVar).

How common is SIX1 p.Arg110= (c.330G>A) in the general population?

SIX1 p.Arg110= (c.330G>A) is rare (popmax 0.234%, afr) (gnomAD).

SIX1 p.Arg110=

c.330G>A · rs73309461 · VCV497460

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.234%, afr)

Conditions

branchiootic syndrome 3

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 -0.65	GERP -3.9, phastCons 0.01
Overall
CADD	10.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.234% African / African-American · 176/75,066 alleles

Filtering AF 0.206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.195%

Overall 0.0116% 187/1,614,234 alleles · rare exomes 83/1,461,868 · genomes 104/152,366 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.234%	427
Admixed American	0.00999%	10,006
Remaining individualsnot grpmax-eligible	0.008%	12,502

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: SIX1
Protein: p.Arg110=
Coding: c.330G>A
MANE Select: NM_005982
dbSNP: rs73309461
Type: single nucleotide variant
Location: chr14:60648860 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.87 · 1 PDB
Residue 110: a UniProt-annotated variant site (in bos3; crucial for interaction with eya1, dna binding and transcription factor activity); an α-helix; a UniProt-annotated variant site (in bos3)

Full SIX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

branchiootic syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: autosomal dominant nonsyndromic hearing loss 23

Similar variants

SIX1 p.Arg110Gln Pathogenic/Likely pathogenic ★★ same residue
SIX1 p.Arg110Trp Pathogenic ★★ same residue
SIX1 p.Arg110Leu Likely pathogenic ★ same residue
SIX1 p.Arg110Gly Uncertain significance ★ ⚠ same residue
SIX1 p.Glu125Lys Pathogenic/Likely pathogenic ★★ same condition
SIX1 p.Tyr129Cys Pathogenic ★★ same condition
SIX1 p.Val106Met Likely pathogenic ★★ same condition
SIX1 p.Ala184Thr 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/six1-p-arg110 (accessed [today's date]).

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