Is CELSR3 p.Arg2099His (c.6296G>A) pathogenic?

CELSR3 p.Arg2099His (c.6296G>A) is classified Uncertain significance in CELSR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-04). AlphaMissense: likely benign (0.1962); Ultra-rare (popmax 0.016%, afr).

How common is CELSR3 p.Arg2099His (c.6296G>A) in the general population?

CELSR3 p.Arg2099His (c.6296G>A) is ultra-rare (popmax 0.016%, afr) (gnomAD).

What do computational predictors say about CELSR3 p.Arg2099His (c.6296G>A)?

AlphaMissense predicts likely benign (score 0.1962) — an in-silico prediction, not a clinical call.

CELSR3 p.Arg2099His

c.6296G>A · VCV3490156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1962 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.016%, afr)

Computational evidence

Protein change
AlphaMissense	0.1962	likely benign
REVEL	0.446	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -0.01, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 12 kb · p 9.5e-43 · regional, not allelic
Overall
CADD	29.8	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 0.016% African / African-American · 12/74,866 alleles

Filtering AF 0.00922% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00722%

Overall 0.00248% 40/1,611,584 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.016%	6,239
Remaining individualsnot grpmax-eligible	0.00481%	20,789
South Asian	0.0022%	45,503
European (non-Finnish)	0.00178%	56,177
Admixed American	0.00167%	59,912
Finnishnot grpmax-eligible	0.00159%	62,714

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: CELSR3
Protein: p.Arg2099His
Coding: c.6296G>A
MANE Select: NM_001407
Type: single nucleotide variant
Location: chr3:48650966 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Residue 2099: the laminin egf-like domain; a disulfide bond

Full CELSR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELSR3 p.Arg2099Cys Conflicting classifications of pathogenicity ★ same residue
CELSR3 p.Ala2862Val Uncertain significance ★★ ⚠ same type
CELSR3 p.Arg2345His Uncertain significance ★★ ⚠ same type
CELSR3 p.Gly2265Ser Uncertain significance ★★ ⚠ same type
CELSR3 p.Phe282Ser Uncertain significance ★★ ⚠ same type
CELSR3 p.Val1107Met Uncertain significance ★★ same type
CELSR3 p.Arg2886= Likely benign ★★ same type
CELSR3 p.Arg3189Gln Benign/Likely benign ★★ 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/celsr3-p-arg2099his (accessed [today's date]).

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