Is CELSR3 p.Pro2000Leu (c.5999C>T) pathogenic?

CELSR3 p.Pro2000Leu (c.5999C>T) is classified Uncertain significance in CELSR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-28). AlphaMissense: likely benign (0.0779); Very rare (popmax 8.56e-05%, nfe).

How common is CELSR3 p.Pro2000Leu (c.5999C>T) in the general population?

CELSR3 p.Pro2000Leu (c.5999C>T) is very rare (popmax 8.56e-05%, nfe) (gnomAD).

What do computational predictors say about CELSR3 p.Pro2000Leu (c.5999C>T)?

AlphaMissense predicts likely benign (score 0.0779) — an in-silico prediction, not a clinical call.

CELSR3 p.Pro2000Leu

c.5999C>T · VCV4225441

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0779 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.56e-05%, nfe)

Computational evidence

Protein change
AlphaMissense	0.0779	likely benign
REVEL	0.315	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 2.4, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 12 kb · p 9.5e-43 · regional, not allelic
Overall
CADD	21.2	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 8.56e-05% European (non-Finnish) · 1/1,168,332 alleles

Overall 6.29e-05% 1/1,589,796 alleles · very rare exomes 1/1,437,452 · genomes 0/152,344 · joint denominator

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: CELSR3
Protein: p.Pro2000Leu
Coding: c.5999C>T
MANE Select: NM_001407
Type: single nucleotide variant
Location: chr3:48651643 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Residue 2000: the egf-like 6; calcium-binding domain

Full CELSR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CELSR3 p.Ala2862Val Uncertain significance ★★ ⚠ same type
CELSR3 p.Arg2345His Uncertain significance ★★ ⚠ same type
CELSR3 p.Gly2265Ser Uncertain significance ★★ ⚠ same type
CELSR3 p.Phe282Ser Uncertain significance ★★ ⚠ same type
CELSR3 p.Val1107Met Uncertain significance ★★ same type
CELSR3 p.Arg2886= Likely benign ★★ same type
CELSR3 p.Arg3189Gln Benign/Likely benign ★★ same type
CELSR3 p.Arg3201Gln Benign ★★ 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/celsr3-p-pro2000leu (accessed [today's date]).

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