Is CELSR2 p.Arg249Cys (c.745C>T) pathogenic?

CELSR2 p.Arg249Cys (c.745C>T) is classified Uncertain significance in CELSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-07). AlphaMissense: likely pathogenic (0.9216); Very rare (popmax 0.00267%, afr).

How common is CELSR2 p.Arg249Cys (c.745C>T) in the general population?

CELSR2 p.Arg249Cys (c.745C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about CELSR2 p.Arg249Cys (c.745C>T)?

AlphaMissense predicts likely pathogenic (score 0.9216) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg249Cys

c.745C>T · rs767957734 · VCV2311289

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9216 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.9216	likely pathogenic
REVEL	0.464	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.88	GERP 0.026, phastCons 0.29
Regional constraint	o/e 0.90	unconstrained · MANE · 1,783 bp · p 0.0042 · regional, not allelic
Overall
CADD	23.1	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 0.00267% African / African-American · 2/74,940 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000372% 6/1,613,926 alleles · very rare exomes 5/1,461,688 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,470
East Asian	0.00223%	44,904
South Asian	0.0011%	91,090
European (non-Finnish)	0.000169%	590,016

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.Arg249Cys
Coding: c.745C>T
MANE Select: NM_001408
dbSNP: rs767957734
Type: single nucleotide variant
Location: chr1:109250824 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 249: the cadherin 1 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-arg249cys (accessed [today's date]).

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