Is SIX3 p.Ser130Pro (c.388T>C) pathogenic?

SIX3 p.Ser130Pro (c.388T>C) is classified Uncertain significance in SIX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-21). AlphaMissense: likely pathogenic (0.9478); Absent from gnomAD v4.1; Associated with SIX3-related disorder.

What condition is associated with SIX3 p.Ser130Pro (c.388T>C)?

SIX3 p.Ser130Pro (c.388T>C) is associated with SIX3-related disorder (ClinVar).

How common is SIX3 p.Ser130Pro (c.388T>C) in the general population?

SIX3 p.Ser130Pro (c.388T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIX3 p.Ser130Pro (c.388T>C)?

AlphaMissense predicts likely pathogenic (score 0.9478) — an in-silico prediction, not a clinical call.

SIX3 p.Ser130Pro

c.388T>C · rs2466514039 · VCV2633570

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9478 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

SIX3-related disorder

Computational evidence

Protein change
AlphaMissense	0.9478	likely pathogenic
REVEL	0.7	pathogenic-leaning
SaProt	LLR -9.76	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 2.1, phastCons 1
Regional constraint	o/e 0.57	unconstrained · MANE · 435 bp · p 5.9e-10 · regional, not allelic
Overall
CADD	32.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: SIX3
Protein: p.Ser130Pro
Coding: c.388T>C
MANE Select: NM_005413
dbSNP: rs2466514039
Type: single nucleotide variant
Location: chr2:44942492 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38

Full SIX3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

SIX3-related disorder

Similar variants

SIX3 p.Ser130Trp Uncertain significance ★ ⚠ same residue
SIX3 p.Pro289Thr Uncertain significance ★★ ⚠ same condition
SIX3 c.806+2T>C Likely pathogenic ★ same condition
SIX3 p.Arg258Trp Likely pathogenic ★ same condition
SIX3 p.Gln241Ter Pathogenic ★ same condition
SIX3 p.Gly287Ser Uncertain significance ★ ⚠ same condition
SIX3 p.Asp331= Likely benign same condition
SIX3 p.Gly33= Likely benign 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/six3-p-ser130pro (accessed [today's date]).

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