Is CELSR2 p.Arg1400His (c.4199G>A) pathogenic?

CELSR2 p.Arg1400His (c.4199G>A) is classified Uncertain significance in CELSR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-07). AlphaMissense: likely benign (0.1082); Rare (popmax 0.116%, afr).

How common is CELSR2 p.Arg1400His (c.4199G>A) in the general population?

CELSR2 p.Arg1400His (c.4199G>A) is rare (popmax 0.116%, afr) (gnomAD).

What do computational predictors say about CELSR2 p.Arg1400His (c.4199G>A)?

AlphaMissense predicts likely benign (score 0.1082) — an in-silico prediction, not a clinical call.

CELSR2 p.Arg1400His

c.4199G>A · rs149106884 · VCV2292603

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1082 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, afr)

Computational evidence

Protein change
AlphaMissense	0.1082	likely benign
REVEL	0.39	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	23.9	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 0.116% African / African-American · 87/75,038 alleles

Filtering AF 0.0963% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0889%

Overall 0.00855% 138/1,614,166 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.116%	863
East Asian	0.0245%	4,081
Remaining individualsnot grpmax-eligible	0.024%	4,167
Admixed American	0.015%	6,670
European (non-Finnish)	0.00127%	78,668
South Asian	0.0011%	91,086

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.Arg1400His
Coding: c.4199G>A
MANE Select: NM_001408
dbSNP: rs149106884
Type: single nucleotide variant
Location: chr1:109261530 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 1400: the laminin g-like 1 domain

Full CELSR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELSR2 p.Arg1400Cys Uncertain significance ★ same residue
CELSR2 p.Arg1400= Likely benign ★ 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

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-arg1400his (accessed [today's date]).

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