Is SIX3 p.Ala136fs (c.406_407del) pathogenic?

SIX3 p.Ala136fs (c.406407del) is classified Pathogenic in SIX3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-04). Very rare (popmax 8.48e-05%, nfe); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Ala136fs (c.406_407del)?

SIX3 p.Ala136fs (c.406_407del) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Ala136fs (c.406_407del) in the general population?

SIX3 p.Ala136fs (c.406_407del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

SIX3 p.Ala136fs

c.406_407del · rs753473749 · VCV449840

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

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 7.8	GERP 2.1, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,584 alleles

Overall 0.000125% 2/1,597,816 alleles · very rare exomes 2/1,445,784 · genomes 0/152,032 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00206%	48,652
European (non-Finnish)grpmax	8.48e-05%	1,179,585

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: SIX3
Protein: p.Ala136fs
Coding: c.406_407del
MANE Select: NM_005413
dbSNP: rs753473749
Type: Microsatellite
Location: chr2:44942500 (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.Gly43del Uncertain significance ★ same condition
SIX3 p.Gly67_Gly69del Uncertain significance ★ same condition
SIX3 p.Gly69_Ser70insGlyGly Conflicting classifications of pathogenicity ★ same condition
SIX3 p.Gly69_Ser70insGlyGlyGly Uncertain significance ★ same condition
SIX3 p.Gly69del Uncertain significance ★ same condition
SIX3 p.Gly69dup Conflicting classifications of pathogenicity ★ same condition
SIX3 p.Ala72Val Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg146Cys 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-ala136fs (accessed [today's date]).

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