Is SIX5 p.Glu96= (c.288G>A) pathogenic?

SIX5 p.Glu96= (c.288G>A) is classified Conflicting classifications of pathogenicity in SIX5 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-06-18). Very rare (popmax 0.00306%, afr); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Glu96= (c.288G>A)?

SIX5 p.Glu96= (c.288G>A) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Glu96= (c.288G>A) in the general population?

SIX5 p.Glu96= (c.288G>A) is very rare (popmax 0.00306%, afr) (gnomAD).

SIX5 p.Glu96=

c.288G>A · VCV3584024

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00306%, afr)

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	GERP 2.1, phastCons 1
Overall
CADD	13.22	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00306% African / African-American · 2/65,338 alleles

Filtering AF 0.000508% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00019%

Overall 0.000406% 5/1,230,500 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00306%	32,669
European (non-Finnish)	0.000278%	359,208

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.Glu96=
Coding: c.288G>A
MANE Select: NM_175875
Type: single nucleotide variant
Location: chr19:45768557 (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-glu96 (accessed [today's date]).

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