Is SIX5 p.Thr591= (c.1773G>T) pathogenic?

SIX5 p.Thr591= (c.1773G>T) is classified Benign/Likely benign in SIX5 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-08). Rare (popmax 0.403%, sas); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Thr591= (c.1773G>T)?

SIX5 p.Thr591= (c.1773G>T) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Thr591= (c.1773G>T) in the general population?

SIX5 p.Thr591= (c.1773G>T) is rare (popmax 0.403%, sas) (gnomAD).

SIX5 p.Thr591=

c.1773G>T · rs138916954 · VCV1285149

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.403%, sas)

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 -14	GERP -3.1
Overall
CADD	0.015	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.403% South Asian · 358/88,754 alleles

Filtering AF 0.369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.355%

Overall 0.0392% 626/1,596,038 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.403%	248
Middle Eastern	0.217%	461
Finnishnot grpmax-eligible	0.146%	686
Admixed American	0.0602%	1,662
Remaining individualsnot grpmax-eligible	0.047%	2,129
European (non-Finnish)	0.00854%	11,709
African / African-American	0.00134%	74,754

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.Thr591=
Coding: c.1773G>T
MANE Select: NM_175875
dbSNP: rs138916954
Type: single nucleotide variant
Location: chr19:45765948 (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.Thr591Met Likely benign ★ same residue
SIX5 p.Thr591Ser Uncertain significance ★ ⚠ same residue
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

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-thr591 (accessed [today's date]).

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