Is SIX5 p.Pro116Arg (c.347C>G) pathogenic?

SIX5 p.Pro116Arg (c.347C>G) is classified Uncertain significance in SIX5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-04-02). AlphaMissense: likely benign (0.3299); No allele count reported in gnomAD v4.1 (AN 1,501,006); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Pro116Arg (c.347C>G)?

SIX5 p.Pro116Arg (c.347C>G) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Pro116Arg (c.347C>G) in the general population?

SIX5 p.Pro116Arg (c.347C>G) is no allele count reported in gnomAD v4.1 (AN 1,501,006) (gnomAD).

What do computational predictors say about SIX5 p.Pro116Arg (c.347C>G)?

AlphaMissense predicts likely benign (score 0.3299) — an in-silico prediction, not a clinical call.

SIX5 p.Pro116Arg

c.347C>G · rs1464692633 · VCV3010143

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3299 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,501,006)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

branchiootorenal syndrome 2

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.3299	likely benign
REVEL	0.298	indeterminate
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.1	GERP -3.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	28.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,501,006). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SIX5
Protein: p.Pro116Arg
Coding: c.347C>G
MANE Select: NM_175875
dbSNP: rs1464692633
Type: single nucleotide variant
Location: chr19:45768498 (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-pro116arg (accessed [today's date]).

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