Is CELSR2 p.Arg444Trp (c.1330C>T) pathogenic?

CELSR2 p.Arg444Trp (c.1330C>T) is classified Uncertain significance in CELSR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-27). AlphaMissense: likely benign (0.2453); Very rare (popmax 0.00329%, sas).

How common is CELSR2 p.Arg444Trp (c.1330C>T) in the general population?

CELSR2 p.Arg444Trp (c.1330C>T) is very rare (popmax 0.00329%, sas) (gnomAD).

What do computational predictors say about CELSR2 p.Arg444Trp (c.1330C>T)?

AlphaMissense predicts likely benign (score 0.2453) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg444Trp

c.1330C>T · rs749186325 · VCV3142023

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2453 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Computational evidence

Protein change
AlphaMissense	0.2453	likely benign
REVEL	0.294	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP -1.5, phastCons 0.98
Regional constraint	o/e 0.90	unconstrained · MANE · 1,783 bp · p 0.0042 · regional, not allelic
Overall
CADD	26.1	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,086 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.0018% 29/1,613,812 alleles · very rare exomes 25/1,461,676 · genomes 4/152,136 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,362
Remaining individualsnot grpmax-eligible	0.0032%	31,241
Finnishnot grpmax-eligible	0.00313%	31,909
European (non-Finnish)	0.00186%	53,638

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.Arg444Trp
Coding: c.1330C>T
MANE Select: NM_001408
dbSNP: rs749186325
Type: single nucleotide variant
Location: chr1:109251409 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 444: the cadherin 3 domain

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-arg444trp (accessed [today's date]).

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