Is SIX1 p.Arg60= (c.180C>G) pathogenic?

SIX1 p.Arg60= (c.180C>G) is classified Benign/Likely benign in SIX1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). Rare (popmax 0.617%, eas); Associated with branchiootic syndrome 3.

What condition is associated with SIX1 p.Arg60= (c.180C>G)?

SIX1 p.Arg60= (c.180C>G) is associated with branchiootic syndrome 3, autosomal dominant nonsyndromic hearing loss 23 (ClinVar).

How common is SIX1 p.Arg60= (c.180C>G) in the general population?

SIX1 p.Arg60= (c.180C>G) is rare (popmax 0.617%, eas) (gnomAD).

SIX1 p.Arg60=

c.180C>G · rs781519092 · VCV313466

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.617%, eas)

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 1.1	GERP -1.8, phastCons 1
Overall
CADD	10.65	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.617% East Asian · 277/44,884 alleles

Filtering AF 0.557% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.534%

Overall 0.0193% 311/1,613,814 alleles · rare exomes 293/1,461,722 · genomes 18/152,092 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.617%	162
Remaining individualsnot grpmax-eligible	0.0496%	2,015
South Asian	0.0011%	91,082
European (non-Finnish)	0.000169%	589,998

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.Arg60=
Coding: c.180C>G
MANE Select: NM_005982
dbSNP: rs781519092
Type: single nucleotide variant
Location: chr14:60649010 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.87 · 1 PDB
Residue 60: an α-helix

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 condition
SIX1 p.Arg110Trp Pathogenic ★★ same condition
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
SIX1 p.Arg119His Uncertain significance ★★ ⚠ same condition
SIX1 p.Arg140Gln 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-arg60 (accessed [today's date]).

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