Is SIX5 p.Leu165Val (c.493C>G) pathogenic?

SIX5 p.Leu165Val (c.493C>G) is classified Uncertain significance in SIX5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.8389); Very rare (popmax 0.0045%, eas); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Leu165Val (c.493C>G)?

SIX5 p.Leu165Val (c.493C>G) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Leu165Val (c.493C>G) in the general population?

SIX5 p.Leu165Val (c.493C>G) is very rare (popmax 0.0045%, eas) (gnomAD).

What do computational predictors say about SIX5 p.Leu165Val (c.493C>G)?

AlphaMissense predicts likely pathogenic (score 0.8389) — an in-silico prediction, not a clinical call.

SIX5 p.Leu165Val

c.493C>G · rs368485758 · VCV2884635

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8389 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0045%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

branchiootorenal syndrome 2

Computational evidence

Protein change
AlphaMissense	0.8389	likely pathogenic
REVEL	0.44	indeterminate
SaProt	LLR -10.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 1.8	GERP -4.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 707 bp · p 0.12 · regional, not allelic
Overall
CADD	25.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Grpmax group 0.0045% East Asian · 2/44,442 alleles

Filtering AF 0.000766% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000608%

Overall 0.00138% 22/1,599,272 alleles · very rare exomes 19/1,447,084 · genomes 3/152,188 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0045%	22,221
Remaining individualsnot grpmax-eligible	0.00323%	30,933
African / African-American	0.00267%	37,390
European (non-Finnish)	0.00128%	78,335
South Asian	0.00111%	89,758

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.Leu165Val
Coding: c.493C>G
MANE Select: NM_175875
dbSNP: rs368485758
Type: single nucleotide variant
Location: chr19:45768352 (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-leu165val (accessed [today's date]).

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