Is SIX5 p.Leu725= (c.2173C>T) pathogenic?

SIX5 p.Leu725= (c.2173C>T) is classified Benign/Likely benign in SIX5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-24). Rare (popmax 0.581%, afr); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Leu725= (c.2173C>T)?

SIX5 p.Leu725= (c.2173C>T) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Leu725= (c.2173C>T) in the general population?

SIX5 p.Leu725= (c.2173C>T) is rare (popmax 0.581%, afr) (gnomAD).

SIX5 p.Leu725=

c.2173C>T · rs112320524 · VCV512355

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.581%, 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 assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 0.44, phastCons 1
Overall
CADD	17.59	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.581% African / African-American · 436/75,072 alleles

Filtering AF 0.536% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.518%

Overall 0.0312% 503/1,613,474 alleles · rare exomes 250/1,461,130 · genomes 253/152,344 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.581%	172
Remaining individualsnot grpmax-eligible	0.0688%	1,453
Middle Eastern	0.0331%	3,018
Admixed American	0.0217%	4,617
European (non-Finnish)	0.000763%	131,113

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.Leu725=
Coding: c.2173C>T
MANE Select: NM_175875
dbSNP: rs112320524
Type: single nucleotide variant
Location: chr19:45765548 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.21

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

Similar variants

SIX5 p.Ala411Val Uncertain significance ★★ ⚠ same condition
SIX5 p.Ala584Val Uncertain significance ★★ ⚠ same condition
SIX5 p.Ala626Thr Uncertain significance ★★ ⚠ same condition
SIX5 p.Ala649Ser Uncertain significance ★★ ⚠ same condition
SIX5 p.Gln483Pro Uncertain significance ★★ ⚠ same condition
SIX5 p.Gly423Arg Uncertain significance ★★ ⚠ same condition
SIX5 p.Gly500Arg Uncertain significance ★★ same condition
SIX5 p.Gly522Arg 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/six5-p-leu725 (accessed [today's date]).

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