Is SIX2 p.Val287Met (c.859G>A) pathogenic?

SIX2 p.Val287Met (c.859G>A) is classified Uncertain significance in SIX2 (ClinVar, Single submitter, 2 submitters; last evaluated 2021-12-07). AlphaMissense: likely pathogenic (0.5914); Ultra-rare (popmax 0.0373%, sas).

How common is SIX2 p.Val287Met (c.859G>A) in the general population?

SIX2 p.Val287Met (c.859G>A) is ultra-rare (popmax 0.0373%, sas) (gnomAD).

What do computational predictors say about SIX2 p.Val287Met (c.859G>A)?

AlphaMissense predicts likely pathogenic (score 0.5914) — an in-silico prediction, not a clinical call.

SIX2 p.Val287Met

c.859G>A · rs773807534 · VCV633690

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5914 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0373%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5914	likely pathogenic
REVEL	0.824	moderately pathogenic-leaning
SaProt	LLR -6.32	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,568 bp · p 0.84 · regional, not allelic
Overall
CADD	28.3	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 0.0373% South Asian · 34/91,088 alleles

Filtering AF 0.0274% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.024%

Overall 0.00465% 75/1,614,092 alleles · ultra-rare exomes 73/1,461,880 · genomes 2/152,212 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0373%	2,679
European (non-Finnish)	0.00347%	28,781

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: SIX2
Protein: p.Val287Met
Coding: c.859G>A
MANE Select: NM_016932
dbSNP: rs773807534
Type: single nucleotide variant
Location: chr2:45006187 (GRCh38)
Gene constraint: LOEUF 1.24 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.99

Full SIX2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SIX2 p.Val287Leu Uncertain significance ★ same residue
SIX2 p.Asn280Ser Uncertain significance ★★ ⚠ same type
SIX2 p.Gly220Val Uncertain significance ★★ ⚠ same type
SIX2 p.Gly261Ser Uncertain significance ★★ ⚠ same type
SIX2 p.Pro235Leu Uncertain significance ★★ ⚠ same type
SIX2 p.Pro236Leu Uncertain significance ★★ ⚠ same type
SIX2 p.Pro250Leu Uncertain significance ★★ ⚠ same type
SIX2 p.Pro258Leu Uncertain significance ★★ ⚠ same type

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/six2-p-val287met (accessed [today's date]).

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