Is CELSR2 p.Arg539Cys (c.1615C>T) pathogenic?

CELSR2 p.Arg539Cys (c.1615C>T) is classified Likely benign in CELSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-21). AlphaMissense: likely benign (0.3012); Ultra-rare (popmax 0.0519%, nfe).

How common is CELSR2 p.Arg539Cys (c.1615C>T) in the general population?

CELSR2 p.Arg539Cys (c.1615C>T) is ultra-rare (popmax 0.0519%, nfe) (gnomAD).

What do computational predictors say about CELSR2 p.Arg539Cys (c.1615C>T)?

AlphaMissense predicts likely benign (score 0.3012) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg539Cys

c.1615C>T · rs138919468 · VCV1656268

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3012 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0519%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3012	likely benign
REVEL	0.404	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 0.95, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 1,783 bp · p 0.0042 · regional, not allelic
Overall
CADD	28.9	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 0.0519% European (non-Finnish) · 612/1,180,020 alleles

Filtering AF 0.0485% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.047%

Overall 0.0408% 659/1,614,094 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0519%	1,928
Remaining individualsnot grpmax-eligible	0.0288%	3,473
South Asian	0.0132%	7,589
African / African-American	0.00933%	10,717
East Asian	0.00668%	14,963
Admixed American	0.005%	20,008
Finnishnot grpmax-eligible	0.00469%	21,332
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608

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.Arg539Cys
Coding: c.1615C>T
MANE Select: NM_001408
dbSNP: rs138919468
Type: single nucleotide variant
Location: chr1:109251694 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 539: the cadherin 4 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-arg539cys (accessed [today's date]).

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