Is SIX5 p.Pro488Ser (c.1462C>T) pathogenic?

SIX5 p.Pro488Ser (c.1462C>T) is classified Conflicting classifications of pathogenicity in SIX5 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.1094); Ultra-rare (popmax 0.0739%, amr); Associated with branchiootorenal syndrome 2.

What condition is associated with SIX5 p.Pro488Ser (c.1462C>T)?

SIX5 p.Pro488Ser (c.1462C>T) is associated with branchiootorenal syndrome 2 (ClinVar).

How common is SIX5 p.Pro488Ser (c.1462C>T) in the general population?

SIX5 p.Pro488Ser (c.1462C>T) is ultra-rare (popmax 0.0739%, amr) (gnomAD).

What do computational predictors say about SIX5 p.Pro488Ser (c.1462C>T)?

AlphaMissense predicts likely benign (score 0.1094) — an in-silico prediction, not a clinical call.

SIX5 p.Pro488Ser

c.1462C>T · rs200487992 · VCV515611

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1094 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0739%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

branchiootorenal syndrome 2

Computational evidence

Protein change
AlphaMissense	0.1094	likely benign
REVEL	0.17	moderately benign-leaning
SaProt	LLR -6.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 2,547 bp · p 3e-11 · regional, not allelic
Overall
CADD	25.1	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 0.0739% Admixed American · 36/48,700 alleles

Filtering AF 0.0549% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0482%

Overall 0.013% 197/1,515,542 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0739%	1,353
Remaining individualsnot grpmax-eligible	0.0137%	7,313
European (non-Finnish)	0.0134%	7,455
African / African-American	0.00276%	36,252

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.Pro488Ser
Coding: c.1462C>T
MANE Select: NM_175875
dbSNP: rs200487992
Type: single nucleotide variant
Location: chr19:45766497 (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-pro488ser (accessed [today's date]).

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