Is SIX3 p.Pro286Ser (c.856C>T) pathogenic?

SIX3 p.Pro286Ser (c.856C>T) is classified Uncertain significance in SIX3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-14). AlphaMissense: likely benign (0.0645); Absent from gnomAD v4.1; Associated with holoprosencephaly 2.

What condition is associated with SIX3 p.Pro286Ser (c.856C>T)?

SIX3 p.Pro286Ser (c.856C>T) is associated with holoprosencephaly 2 (ClinVar).

How common is SIX3 p.Pro286Ser (c.856C>T) in the general population?

SIX3 p.Pro286Ser (c.856C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about SIX3 p.Pro286Ser (c.856C>T)?

AlphaMissense predicts likely benign (score 0.0645) — an in-silico prediction, not a clinical call.

SIX3 p.Pro286Ser

c.856C>T · rs2466518476 · VCV2845725

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0645 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,574,076)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

holoprosencephaly 2

Computational evidence

Protein change
AlphaMissense	0.0645	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -6.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP -0.2, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 189 bp · p 0.083 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,574,076). 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.Pro286Ser
Coding: c.856C>T
MANE Select: NM_005413
dbSNP: rs2466518476
Type: single nucleotide variant
Location: chr2:44944617 (GRCh38)
Gene constraint: LOEUF 0.387 · pLI 0.99 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 70.38
Residue 286: 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-pro286ser (accessed [today's date]).

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