Is SIX5 p.Pro441Ser (c.1321C>T) pathogenic?

SIX5 p.Pro441Ser (c.1321C>T) is classified Conflicting classifications of pathogenicity in SIX5 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-06-15). AlphaMissense: likely benign (0.0712); Very rare (popmax 0.00189%, nfe); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Pro441Ser (c.1321C>T)?

SIX5 p.Pro441Ser (c.1321C>T) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Pro441Ser (c.1321C>T) in the general population?

SIX5 p.Pro441Ser (c.1321C>T) is very rare (popmax 0.00189%, nfe) (gnomAD).

What do computational predictors say about SIX5 p.Pro441Ser (c.1321C>T)?

AlphaMissense predicts likely benign (score 0.0712) — an in-silico prediction, not a clinical call.

SIX5 p.Pro441Ser

c.1321C>T · rs930795278 · VCV2472918

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0712 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00189%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

branchiootorenal syndrome 2

Computational evidence

Protein change
AlphaMissense	0.0712	likely benign
REVEL	0.218	benign-leaning
SaProt	LLR -6.54	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.92	GERP -2.1, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,547 bp · p 3e-11 · regional, not allelic
Overall
CADD	12.34	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 0.00189% European (non-Finnish) · 21/1,111,764 alleles

Filtering AF 0.00121% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00103%

Overall 0.00149% 22/1,476,942 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00189%	52,941
Remaining individualsnot grpmax-eligible	0.00176%	56,892

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.Pro441Ser
Coding: c.1321C>T
MANE Select: NM_175875
dbSNP: rs930795278
Type: single nucleotide variant
Location: chr19:45766638 (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.Pro441= Uncertain significance ★ same residue
SIX5 p.Pro441Leu 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

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-pro441ser (accessed [today's date]).

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