Is SIX3 p.Ser296Trp (c.887C>G) pathogenic?

SIX3 p.Ser296Trp (c.887C>G) is classified Uncertain significance in SIX3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-21). AlphaMissense: ambiguous (0.4604); Ultra-rare (popmax 0.0154%, nfe); Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Ser296Trp (c.887C>G)?

SIX3 p.Ser296Trp (c.887C>G) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Ser296Trp (c.887C>G) in the general population?

SIX3 p.Ser296Trp (c.887C>G) is ultra-rare (popmax 0.0154%, nfe) (gnomAD).

What do computational predictors say about SIX3 p.Ser296Trp (c.887C>G)?

AlphaMissense predicts ambiguous (score 0.4604) — an in-silico prediction, not a clinical call.

SIX3 p.Ser296Trp

c.887C>G · rs751280287 · VCV532826

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4604 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0154%, nfe)

Conditions

holoprosencephaly 2

Computational evidence

Protein change
AlphaMissense	0.4604	ambiguous
REVEL	0.601	indeterminate
SaProt	LLR -9.85	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP -0.92, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 189 bp · p 0.083 · 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

Grpmax group 0.0154% European (non-Finnish) · 180/1,167,956 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0128%

Overall 0.0119% 187/1,574,258 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0154%	6,489
Remaining individualsnot grpmax-eligible	0.00653%	15,323
Admixed American	0.00349%	28,677
Finnishnot grpmax-eligible	0.00214%	46,640

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.Ser296Trp
Coding: c.887C>G
MANE Select: NM_005413
dbSNP: rs751280287
Type: single nucleotide variant
Location: chr2:44944648 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 296: the 'disordered' region

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.Ala72Val Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg146Cys Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg201His Uncertain significance ★★ ⚠ same condition
SIX3 p.Arg281Ser Uncertain significance ★★ same condition
SIX3 p.Asp205His Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly103Arg Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly244Cys Uncertain significance ★★ ⚠ same condition
SIX3 p.Gly317Ser 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-ser296trp (accessed [today's date]).

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