Is SIX5 p.Pro424= (c.1272C>T) pathogenic?

SIX5 p.Pro424= (c.1272C>T) is classified Uncertain significance in SIX5 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-02-19). Very rare (popmax 8.84e-05%, nfe); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Pro424= (c.1272C>T)?

SIX5 p.Pro424= (c.1272C>T) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Pro424= (c.1272C>T) in the general population?

SIX5 p.Pro424= (c.1272C>T) is very rare (popmax 8.84e-05%, nfe) (gnomAD).

SIX5 p.Pro424=

c.1272C>T · rs1179130122 · VCV3029619

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 8.84e-05%, nfe)

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 2	GERP 0.49, phastCons 1
Overall
CADD	5.44	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.84e-05% European (non-Finnish) · 1/1,131,164 alleles

Overall 6.6e-05% 1/1,514,528 alleles · very rare exomes 1/1,362,262 · genomes 0/152,266 · joint denominator

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.Pro424=
Coding: c.1272C>T
MANE Select: NM_175875
dbSNP: rs1179130122
Type: single nucleotide variant
Location: chr19:45766687 (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-pro424 (accessed [today's date]).

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