Is SIX1 p.Phe75= (c.225C>T) pathogenic?

SIX1 p.Phe75= (c.225C>T) is classified Likely benign in SIX1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-20). Very rare (popmax 0.000932%, nfe); Associated with autosomal dominant nonsyndromic hearing loss 23.

What condition is associated with SIX1 p.Phe75= (c.225C>T)?

SIX1 p.Phe75= (c.225C>T) is associated with autosomal dominant nonsyndromic hearing loss 23, branchiootic syndrome 3 (ClinVar).

How common is SIX1 p.Phe75= (c.225C>T) in the general population?

SIX1 p.Phe75= (c.225C>T) is very rare (popmax 0.000932%, nfe) (gnomAD).

SIX1 p.Phe75=

c.225C>T · rs1291757623 · VCV2154445

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

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 3.6	GERP -0.24, phastCons 1
Overall
CADD	12.02	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,180,034 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000681% 11/1,614,096 alleles · very rare

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.Phe75=
Coding: c.225C>T
MANE Select: NM_005982
dbSNP: rs1291757623
Type: single nucleotide variant
Location: chr14:60648965 (GRCh38)
Gene constraint: LOEUF 0.692 · pLI 0.26 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.87 · 1 PDB

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.Phe75Leu Uncertain significance ★ ⚠ 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-phe75 (accessed [today's date]).

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