Is SIX5 p.Leu348= (c.1042C>T) pathogenic?

SIX5 p.Leu348= (c.1042C>T) is classified Benign/Likely benign in SIX5 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-19). Rare (popmax 0.261%, amr); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Leu348= (c.1042C>T)?

SIX5 p.Leu348= (c.1042C>T) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Leu348= (c.1042C>T) in the general population?

SIX5 p.Leu348= (c.1042C>T) is rare (popmax 0.261%, amr) (gnomAD).

SIX5 p.Leu348=

c.1042C>T · rs779368770 · VCV668435

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.261%, amr)

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 1.4	GERP 0.29, phastCons 1
Overall
CADD	7.263	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.261% Admixed American · 138/52,970 alleles

Filtering AF 0.225% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.212%

Overall 0.0091% 142/1,560,186 alleles · rare exomes 122/1,407,988 · genomes 20/152,198 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.261%	384
Remaining individualsnot grpmax-eligible	0.00331%	30,242
South Asian	0.00117%	85,502
European (non-Finnish)	8.66e-05%	1,155,365

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.Leu348=
Coding: c.1042C>T
MANE Select: NM_175875
dbSNP: rs779368770
Type: single nucleotide variant
Location: chr19:45766917 (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-leu348 (accessed [today's date]).

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