Is CELSR2 p.His585Arg (c.1754A>G) pathogenic?

CELSR2 p.His585Arg (c.1754A>G) is classified Benign in CELSR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-24). AlphaMissense: likely benign (0.0858); Low-frequency (popmax 1.09%, afr).

How common is CELSR2 p.His585Arg (c.1754A>G) in the general population?

CELSR2 p.His585Arg (c.1754A>G) is low-frequency (popmax 1.09%, afr) (gnomAD).

What do computational predictors say about CELSR2 p.His585Arg (c.1754A>G)?

AlphaMissense predicts likely benign (score 0.0858) — an in-silico prediction, not a clinical call.

CELSR2 p.His585Arg

c.1754A>G · rs115030739 · VCV735873

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0858 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.09%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0858	likely benign
REVEL	0.219	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 1,783 bp · p 0.0042 · regional, not allelic
Overall
CADD	23.0	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 1.09% African / African-American · 816/75,010 alleles

Filtering AF 1.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 1%

Overall 0.056% 904/1,614,068 alleles · low-frequency exomes 407/1,461,844 · genomes 497/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.09%	92
Remaining individualsnot grpmax-eligible	0.064%	1,562
Admixed American	0.0383%	2,609
Middle Eastern	0.033%	3,031
European (non-Finnish)	0.00195%	51,305

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.His585Arg
Coding: c.1754A>G
MANE Select: NM_001408
dbSNP: rs115030739
Type: single nucleotide variant
Location: chr1:109251833 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 585: 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-his585arg (accessed [today's date]).

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