Is CELSR2 p.Arg1066Trp (c.3196C>T) pathogenic?

CELSR2 p.Arg1066Trp (c.3196C>T) is classified Uncertain significance in CELSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-13). AlphaMissense: likely benign (0.149); Ultra-rare (popmax 0.0156%, eas).

How common is CELSR2 p.Arg1066Trp (c.3196C>T) in the general population?

CELSR2 p.Arg1066Trp (c.3196C>T) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about CELSR2 p.Arg1066Trp (c.3196C>T)?

AlphaMissense predicts likely benign (score 0.149) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg1066Trp

c.3196C>T · rs566212338 · VCV3014978

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.149 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.149	likely benign
REVEL	0.241	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 1.4	GERP 0.95, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 6,488 bp · p 1.6e-09 · regional, not allelic
Overall
CADD	24.6	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 0.0156% East Asian · 7/44,886 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00514%

Overall 0.00254% 41/1,613,432 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,412
Finnishnot grpmax-eligible	0.00948%	10,547
South Asian	0.00878%	11,385
African / African-American	0.004%	25,015
Remaining individualsnot grpmax-eligible	0.0032%	31,251
European (non-Finnish)	0.00127%	78,668

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.Arg1066Trp
Coding: c.3196C>T
MANE Select: NM_001408
dbSNP: rs566212338
Type: single nucleotide variant
Location: chr1:109253275 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 1066: the cadherin 9 domain; a UniProt-annotated variant site (in)

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

Similar variants

CELSR2 p.Arg1066Gln Benign ★★ same residue
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

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-arg1066trp (accessed [today's date]).

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