Is SIX5 p.Val183= (c.549G>A) pathogenic?

SIX5 p.Val183= (c.549G>A) is classified Benign/Likely benign in SIX5 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-08). Rare (popmax 0.268%, afr); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Val183= (c.549G>A)?

SIX5 p.Val183= (c.549G>A) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Val183= (c.549G>A) in the general population?

SIX5 p.Val183= (c.549G>A) is rare (popmax 0.268%, afr) (gnomAD).

SIX5 p.Val183=

c.549G>A · rs143904307 · VCV596384

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.268%, 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 4.7	GERP 2.1, phastCons 1
Overall
CADD	14.48	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.268% African / African-American · 201/75,024 alleles

Filtering AF 0.238% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.226%

Overall 0.0148% 239/1,611,562 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.268%	373
Middle Eastern	0.033%	3,031
Admixed American	0.0234%	4,271
Remaining individualsnot grpmax-eligible	0.0112%	8,909
European (non-Finnish)	0.00127%	78,615

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.Val183=
Coding: c.549G>A
dbSNP: rs143904307
Type: single nucleotide variant
Location: chr19:45768296 (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-val183 (accessed [today's date]).

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