Is SIX5 p.Phe647Cys (c.1940T>G) pathogenic?

SIX5 p.Phe647Cys (c.1940T>G) is classified Uncertain significance in SIX5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-14). AlphaMissense: ambiguous (0.4533); Very rare (popmax 0.00133%, afr); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Phe647Cys (c.1940T>G)?

SIX5 p.Phe647Cys (c.1940T>G) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Phe647Cys (c.1940T>G) in the general population?

SIX5 p.Phe647Cys (c.1940T>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about SIX5 p.Phe647Cys (c.1940T>G)?

AlphaMissense predicts ambiguous (score 0.4533) — an in-silico prediction, not a clinical call.

SIX5 p.Phe647Cys

c.1940T>G · rs1969057144 · VCV2630886

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4533 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

branchiootorenal syndrome 2

Computational evidence

Protein change
AlphaMissense	0.4533	ambiguous
REVEL	0.274	benign-leaning
SaProt	LLR -6.48	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,547 bp · p 3e-11 · regional, not allelic
Overall
CADD	19.23	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/74,986 alleles

Overall 6.22e-05% 1/1,607,532 alleles · very rare exomes 1/1,455,392 · genomes 0/152,140 · 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.Phe647Cys
Coding: c.1940T>G
MANE Select: NM_175875
dbSNP: rs1969057144
Type: single nucleotide variant
Location: chr19:45765781 (GRCh38)
Gene constraint: LOEUF 1.08 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.21
Residue 647: the 'disordered' region

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.Phe647Leu Uncertain significance ★ ⚠ same residue
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

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-phe647cys (accessed [today's date]).

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