Is SIX3 p.Pro187fs (c.556_557dup) pathogenic?

SIX3 p.Pro187fs (c.556557dup) is classified Pathogenic in SIX3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2000-10-01). Absent from gnomAD; Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Pro187fs (c.556_557dup)?

SIX3 p.Pro187fs (c.556_557dup) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Pro187fs (c.556_557dup) in the general population?

SIX3 p.Pro187fs (c.556_557dup) is absent from gnomAD (gnomAD).

SIX3 p.Pro187fs

c.556_557dup · rs1572624159 · VCV6096

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

holoprosencephaly 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 1 of 2
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.22	GERP -4.2, phastCons 0.22

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: SIX3
Protein: p.Pro187fs
Coding: c.556_557dup
MANE Select: NM_005413
dbSNP: rs1572624159
Type: Duplication
Location: chr2:44942659 (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

holoprosencephaly 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

SIX3 p.Glu101_Thr102insMetGluGlu Uncertain significance ★ same condition
SIX3 p.Gly42_Gly47dup Conflicting classifications of pathogenicity ★ same condition
SIX3 p.Gly47_Ser48insAlaGlyGlyGly Uncertain significance ★ same condition
SIX3 p.Gly47_Ser48insGlyGlyAlaGlyGlyGly Uncertain significance ★ same condition
SIX3 p.Pro187Ala Uncertain significance ★ ⚠ same residue
SIX3 p.Pro187= Likely benign ★ same residue
SIX3 p.Ala136fs Pathogenic ★★ same condition
SIX3 p.Ala72Val 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/six3-p-pro187fs (accessed [today's date]).

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