Is SIX5 p.Pro5= (c.15T>G) pathogenic?

SIX5 p.Pro5= (c.15T>G) is classified Likely benign in SIX5 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-08). Ultra-rare (popmax 0.0105%, nfe); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Pro5= (c.15T>G)?

SIX5 p.Pro5= (c.15T>G) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Pro5= (c.15T>G) in the general population?

SIX5 p.Pro5= (c.15T>G) is ultra-rare (popmax 0.0105%, nfe) (gnomAD).

SIX5 p.Pro5=

c.15T>G · rs1366167968 · VCV1580218

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0105%, nfe)

Conditions

branchiootorenal syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 2.9	GERP 0.59, phastCons 1
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0105% European (non-Finnish) · 120/1,140,846 alleles

Filtering AF 0.00897% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00839%

Overall 0.00854% 130/1,523,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0105%	9,507
Admixed American	0.00599%	16,703
African / African-American	0.00557%	17,942
Remaining individualsnot grpmax-eligible	0.00337%	29,641
South Asian	0.00121%	82,708

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: SIX5
Protein: p.Pro5=
Coding: c.15T>G
dbSNP: rs1366167968
Type: single nucleotide variant
Location: chr19:45768830 (GRCh38)

Full SIX5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

branchiootorenal syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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/six5-p-pro5 (accessed [today's date]).

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