Is CELSR2 p.Val2287Ile (c.6859G>A) pathogenic?

CELSR2 p.Val2287Ile (c.6859G>A) is classified Uncertain significance in CELSR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-04-24). AlphaMissense: likely benign (0.077); Rare (popmax 0.214%, nfe); Associated with idiopathic scoliosis.

What condition is associated with CELSR2 p.Val2287Ile (c.6859G>A)?

CELSR2 p.Val2287Ile (c.6859G>A) is associated with idiopathic scoliosis (ClinVar).

How common is CELSR2 p.Val2287Ile (c.6859G>A) in the general population?

CELSR2 p.Val2287Ile (c.6859G>A) is rare (popmax 0.214%, nfe) (gnomAD).

What do computational predictors say about CELSR2 p.Val2287Ile (c.6859G>A)?

AlphaMissense predicts likely benign (score 0.077) — an in-silico prediction, not a clinical call.

CELSR2 p.Val2287Ile

c.6859G>A · rs141489111 · VCV397652

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.077 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.214%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

idiopathic scoliosis

Computational evidence

Protein change
AlphaMissense	0.077	likely benign
REVEL	0.062	moderately benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	20.7	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

Grpmax group 0.214% European (non-Finnish) · 2,520/1,180,008 alleles

Filtering AF 0.207% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.204%

Overall 0.166% 2,676/1,613,936 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.214%	468
Ashkenazi Jewishnot grpmax-eligible	0.128%	779
Remaining individualsnot grpmax-eligible	0.0992%	1,008
African / African-American	0.0414%	2,417
Admixed American	0.0317%	3,158
Middle Eastern	0.0164%	6,084
East Asian	0.00445%	22,448
South Asian	0.00329%	30,363

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: CELSR2
Protein: p.Val2287Ile
Coding: c.6859G>A
MANE Select: NM_001408
dbSNP: rs141489111
Type: single nucleotide variant
Location: chr1:109269470 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 2287: the gain-b domain

Full CELSR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

idiopathic scoliosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CELSR2 c.8338+1G>C Uncertain significance ★★ same type
CELSR2 p.Ala1114Val Uncertain significance ★★ ⚠ same type
CELSR2 p.Ala2145Thr Uncertain significance ★★ ⚠ same type
CELSR2 p.Ala2574Thr Uncertain significance ★★ ⚠ same type
CELSR2 p.Arg1171Gln Uncertain significance ★★ ⚠ same type
CELSR2 p.Arg1328His Uncertain significance ★★ ⚠ same type
CELSR2 p.Arg1400His Uncertain significance ★★ same type
CELSR2 p.Arg1978Gln 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/celsr2-p-val2287ile (accessed [today's date]).

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