Is CELSR2 p.Arg1066Gln (c.3197G>A) pathogenic?

CELSR2 p.Arg1066Gln (c.3197G>A) is classified Benign in CELSR2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-25). AlphaMissense: likely benign (0.065); Low-frequency (popmax 1.91%, afr).

How common is CELSR2 p.Arg1066Gln (c.3197G>A) in the general population?

CELSR2 p.Arg1066Gln (c.3197G>A) is low-frequency (popmax 1.91%, afr) (gnomAD).

What do computational predictors say about CELSR2 p.Arg1066Gln (c.3197G>A)?

AlphaMissense predicts likely benign (score 0.065) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg1066Gln

c.3197G>A · rs12083590 · VCV777929

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.065 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.91%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.065	likely benign
REVEL	0.031	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 7.7	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	21.1	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 1.91% African / African-American · 1,430/75,060 alleles

Filtering AF 1.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.79%

Overall 0.131% 2,113/1,613,474 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.91%	52
Middle Eastern	0.33%	303
Admixed American	0.29%	345
Remaining individualsnot grpmax-eligible	0.182%	548
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
European (non-Finnish)	0.0293%	3,411
South Asian	0.0209%	4,794
East Asian	0.00223%	44,894

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.Arg1066Gln
Coding: c.3197G>A
MANE Select: NM_001408
dbSNP: rs12083590
Type: single nucleotide variant
Location: chr1:109253276 (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.Arg1066Trp Uncertain significance ★ ⚠ 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-arg1066gln (accessed [today's date]).

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