Is SIX1 p.Pro149= (c.447A>G) pathogenic?

SIX1 p.Pro149= (c.447A>G) is classified Likely benign in SIX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-12). Absent from gnomAD v4.1; Associated with autosomal dominant nonsyndromic hearing loss 23.

What condition is associated with SIX1 p.Pro149= (c.447A>G)?

SIX1 p.Pro149= (c.447A>G) is associated with autosomal dominant nonsyndromic hearing loss 23, branchiootic syndrome 3 (ClinVar).

How common is SIX1 p.Pro149= (c.447A>G) in the general population?

SIX1 p.Pro149= (c.447A>G) is absent from gnomAD v4.1 (gnomAD).

SIX1 p.Pro149=

c.447A>G · rs2502643736 · VCV2129803

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

autosomal dominant nonsyndromic hearing loss 23

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 -1.5	GERP -4.1
Overall
CADD	11.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SIX1
Protein: p.Pro149=
Coding: c.447A>G
MANE Select: NM_005982
dbSNP: rs2502643736
Type: single nucleotide variant
Location: chr14:60648743 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.87 · 1 PDB
Residue 149: a DNA-binding region

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

Disease context

autosomal dominant nonsyndromic hearing loss 23 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: branchiootic syndrome 3

Similar variants

SIX1 p.Pro149fs Conflicting classifications of pathogenicity ★ same residue
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

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-pro149 (accessed [today's date]).

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