Is CELSR1 p.Glu404Asp (c.1212G>C) pathogenic?

CELSR1 p.Glu404Asp (c.1212G>C) is classified Uncertain significance in CELSR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-02). AlphaMissense: likely benign (0.1244); Very rare (popmax 8.48e-05%, nfe).

How common is CELSR1 p.Glu404Asp (c.1212G>C) in the general population?

CELSR1 p.Glu404Asp (c.1212G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CELSR1 p.Glu404Asp (c.1212G>C)?

AlphaMissense predicts likely benign (score 0.1244) — an in-silico prediction, not a clinical call.

CELSR1 p.Glu404Asp

c.1212G>C · rs2518412198 · VCV2615497

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1244 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.1244	likely benign
REVEL	0.018	moderately 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 -5	GERP -3.9
Regional constraint	o/e 1.06	unconstrained · MANE · 1,320 bp · p 0.15 · regional, not allelic
Overall
CADD	6.469	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,890 alleles

Overall 6.86e-05% 1/1,457,934 alleles · very rare

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: CELSR1
Protein: p.Glu404Asp
Coding: c.1212G>C
MANE Select: NM_001378328
dbSNP: rs2518412198
Type: single nucleotide variant
Location: chr22:46535959 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 404: a UniProt-annotated variant site (in lmphm9); the cadherin 2 domain

Full CELSR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELSR1 p.Glu404Lys Uncertain significance ★★ ⚠ same residue
CELSR1 p.Glu404Gln Uncertain significance ★ ⚠ same residue
ME2 p.Ile404Val Uncertain significance ★ ⚠ same residue
CELSR1 p.Ala2442Val Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala2955Thr Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala396Ser Uncertain significance ★★ ⚠ same type
CELSR1 p.Ala617Ser Uncertain significance ★★ ⚠ same type
CELSR1 p.Arg1323Gln 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/celsr1-p-glu404asp (accessed [today's date]).

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