Is CELSR2 p.Arg1990His (c.5969G>A) pathogenic?

CELSR2 p.Arg1990His (c.5969G>A) is classified Uncertain significance in CELSR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-23). AlphaMissense: likely benign (0.1997); Rare (popmax 0.18%, eas).

How common is CELSR2 p.Arg1990His (c.5969G>A) in the general population?

CELSR2 p.Arg1990His (c.5969G>A) is rare (popmax 0.18%, eas) (gnomAD).

What do computational predictors say about CELSR2 p.Arg1990His (c.5969G>A)?

AlphaMissense predicts likely benign (score 0.1997) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg1990His

c.5969G>A · VCV4737563

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1997 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.18%, eas)

Computational evidence

Protein change
AlphaMissense	0.1997	likely benign
REVEL	0.389	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 0.81, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	26.8	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 0.18% East Asian · 81/44,886 alleles

Filtering AF 0.149% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.137%

Overall 0.00781% 126/1,614,088 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.18%	554
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.008%	12,502
African / African-American	0.00666%	15,006
South Asian	0.00329%	30,363
European (non-Finnish)	0.00263%	38,066

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.Arg1990His
Coding: c.5969G>A
MANE Select: NM_001408
Type: single nucleotide variant
Location: chr1:109266162 (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 p.Arg1990Cys Uncertain significance ★ same residue
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

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-arg1990his (accessed [today's date]).

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