Is CELSR2 p.Arg1876His (c.5627G>A) pathogenic?

CELSR2 p.Arg1876His (c.5627G>A) is classified Uncertain significance in CELSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-18). AlphaMissense: likely benign (0.1627); Ultra-rare (popmax 0.0168%, amr).

How common is CELSR2 p.Arg1876His (c.5627G>A) in the general population?

CELSR2 p.Arg1876His (c.5627G>A) is ultra-rare (popmax 0.0168%, amr) (gnomAD).

What do computational predictors say about CELSR2 p.Arg1876His (c.5627G>A)?

AlphaMissense predicts likely benign (score 0.1627) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg1876His

c.5627G>A · rs141367242 · VCV2525926

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1627 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, amr)

Computational evidence

Protein change
AlphaMissense	0.1627	likely benign
REVEL	0.407	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	25.2	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 0.0168% Admixed American · 10/59,508 alleles

Filtering AF 0.0111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0104%

Overall 0.0108% 173/1,608,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0168%	5,951
European (non-Finnish)	0.0127%	7,843
East Asian	0.0111%	8,970
Remaining individualsnot grpmax-eligible	0.00482%	20,735
African / African-American	0.00401%	24,934
Finnishnot grpmax-eligible	0.00157%	63,846
South Asian	0.00111%	90,248

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.Arg1876His
Coding: c.5627G>A
MANE Select: NM_001408
dbSNP: rs141367242
Type: single nucleotide variant
Location: chr1:109265211 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)

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-arg1876his (accessed [today's date]).

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