Is CELSR3 p.Arg753Trp (c.2257C>T) pathogenic?

CELSR3 p.Arg753Trp (c.2257C>T) is classified Likely benign in CELSR3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-09-26). AlphaMissense: likely benign (0.1738); Rare (popmax 0.162%, amr); Associated with CELSR3-related disorder.

What condition is associated with CELSR3 p.Arg753Trp (c.2257C>T)?

CELSR3 p.Arg753Trp (c.2257C>T) is associated with CELSR3-related disorder (ClinVar).

How common is CELSR3 p.Arg753Trp (c.2257C>T) in the general population?

CELSR3 p.Arg753Trp (c.2257C>T) is rare (popmax 0.162%, amr) (gnomAD).

What do computational predictors say about CELSR3 p.Arg753Trp (c.2257C>T)?

AlphaMissense predicts likely benign (score 0.1738) — an in-silico prediction, not a clinical call.

CELSR3 p.Arg753Trp

c.2257C>T · rs193020039 · VCV3032532

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1738 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.162%, amr)

Conditions

CELSR3-related disorder

Computational evidence

Protein change
AlphaMissense	0.1738	likely benign
REVEL	0.306	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 541 bp · p 0.092 · regional, not allelic
Overall
CADD	25.6	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 0.162% Admixed American · 97/60,016 alleles

Filtering AF 0.136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.126%

Overall 0.00756% 122/1,614,096 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.162%	619
South Asian	0.0176%	5,693
Remaining individualsnot grpmax-eligible	0.0032%	31,252
African / African-American	0.00133%	75,014
European (non-Finnish)	0.000508%	196,670

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.Arg753Trp
Coding: c.2257C>T
MANE Select: NM_001407
dbSNP: rs193020039
Type: single nucleotide variant
Location: chr3:48660378 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Residue 753: the cadherin 4 domain

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

Disease context

CELSR3-related disorder

Similar variants

CELSR3 p.Arg753Gln Uncertain significance ★ ⚠ 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-arg753trp (accessed [today's date]).

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