Is CELSR2 p.Arg2820Gln (c.8459G>A) pathogenic?

CELSR2 p.Arg2820Gln (c.8459G>A) is classified Uncertain significance in CELSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0677); Ultra-rare (popmax 0.0455%, sas).

How common is CELSR2 p.Arg2820Gln (c.8459G>A) in the general population?

CELSR2 p.Arg2820Gln (c.8459G>A) is ultra-rare (popmax 0.0455%, sas) (gnomAD).

What do computational predictors say about CELSR2 p.Arg2820Gln (c.8459G>A)?

AlphaMissense predicts likely benign (score 0.0677) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg2820Gln

c.8459G>A · VCV4225331

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0677 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0455%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Computational evidence

Protein change
AlphaMissense	0.0677	likely benign
REVEL	0.132	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 8.2	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	19.83	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 0.0455% South Asian · 41/90,022 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0306%

Overall 0.00336% 54/1,605,144 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0455%	2,196
East Asian	0.0112%	8,957
Remaining individualsnot grpmax-eligible	0.00484%	20,668
Admixed American	0.0034%	29,393
African / African-American	0.00134%	74,712
European (non-Finnish)	0.00017%	587,720

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.Arg2820Gln
Coding: c.8459G>A
MANE Select: NM_001408
Type: single nucleotide variant
Location: chr1:109273286 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 2820: the 'disordered' region

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

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-arg2820gln (accessed [today's date]).

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