Is CELSR3 p.Pro2990Arg (c.8969C>G) pathogenic?

CELSR3 p.Pro2990Arg (c.8969C>G) is classified Benign in CELSR3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-29). AlphaMissense: likely benign (0.0842); Rare (popmax 0.76%, eas); Associated with CELSR3-related disorder.

What condition is associated with CELSR3 p.Pro2990Arg (c.8969C>G)?

CELSR3 p.Pro2990Arg (c.8969C>G) is associated with CELSR3-related disorder (ClinVar).

How common is CELSR3 p.Pro2990Arg (c.8969C>G) in the general population?

CELSR3 p.Pro2990Arg (c.8969C>G) is rare (popmax 0.76%, eas) (gnomAD).

What do computational predictors say about CELSR3 p.Pro2990Arg (c.8969C>G)?

AlphaMissense predicts likely benign (score 0.0842) — an in-silico prediction, not a clinical call.

CELSR3 p.Pro2990Arg

c.8969C>G · rs138606642 · VCV3049314

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0842 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.76%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

CELSR3-related disorder

Computational evidence

Protein change
AlphaMissense	0.0842	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 6.1	GERP 0.1, phastCons 0.99
Regional constraint	o/e 0.92	unconstrained · MANE · 10 kb · p 0.0024 · regional, not allelic
Overall
CADD	18.75	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 0.76% East Asian · 341/44,872 alleles

Filtering AF 0.694% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.667%

Overall 0.0256% 413/1,612,548 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.76%	132
Remaining individualsnot grpmax-eligible	0.0736%	1,358
Middle Eastern	0.0167%	5,984
South Asian	0.0132%	7,589
African / African-American	0.012%	8,335
Admixed American	0.00167%	60,012
European (non-Finnish)	0.000254%	393,260

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.Pro2990Arg
Coding: c.8969C>G
MANE Select: NM_001407
dbSNP: rs138606642
Type: single nucleotide variant
Location: chr3:48641380 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Residue 2990: the 'disordered' region

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

Disease context

CELSR3-related disorder

Similar variants

CELSR3 p.Pro2990= Likely benign same residue
CELSR3 p.Phe282Ser Uncertain significance ★★ ⚠ same condition
CELSR3 p.Cys1502Tyr Uncertain significance ★ ⚠ same condition
CELSR3 p.Ala3148Glu Uncertain significance ⚠ same condition
CELSR3 c.7464-9T>C Likely benign same condition
CELSR3 c.8086-5T>G Likely benign same condition
CELSR3 c.8165+7T>C Likely benign same condition
CELSR3 c.9912-8G>A Likely benign same condition

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-pro2990arg (accessed [today's date]).

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