Is CELSR1 p.Ser533Ile (c.1598G>T) pathogenic?

CELSR1 p.Ser533Ile (c.1598G>T) is classified Uncertain significance in CELSR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-04). AlphaMissense: likely benign (0.1417); Very rare (popmax 0.00133%, afr); Associated with CELSR1-related disorder.

What condition is associated with CELSR1 p.Ser533Ile (c.1598G>T)?

CELSR1 p.Ser533Ile (c.1598G>T) is associated with CELSR1-related disorder (ClinVar).

How common is CELSR1 p.Ser533Ile (c.1598G>T) in the general population?

CELSR1 p.Ser533Ile (c.1598G>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about CELSR1 p.Ser533Ile (c.1598G>T)?

AlphaMissense predicts likely benign (score 0.1417) — an in-silico prediction, not a clinical call.

CELSR1 p.Ser533Ile

c.1598G>T · rs2518410577 · VCV2630573

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1417 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

CELSR1-related disorder

Computational evidence

Protein change
AlphaMissense	0.1417	likely benign
REVEL	0.196	benign-leaning
SaProt	LLR -5.25	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.71	unconstrained · MANE · 420 bp · p 6.6e-05 · regional, not allelic
Overall
CADD	22.3	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,060 alleles

Overall 6.2e-05% 1/1,613,440 alleles · very rare exomes 1/1,461,110 · genomes 0/152,330 · 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: CELSR1
Protein: p.Ser533Ile
Coding: c.1598G>T
MANE Select: NM_001378328
dbSNP: rs2518410577
Type: single nucleotide variant
Location: chr22:46535573 (GRCh38)
Gene constraint: LOEUF 0.564 · pLI <0.01 (gnomAD)
Residue 533: a UniProt-annotated variant site (in lmphm9); the cadherin 3 domain

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

Disease context

CELSR1-related disorder

Similar variants

ME2 p.Tyr533= Likely benign ★ same residue
CELSR1 p.Arg1643Gln Uncertain significance ★★ ⚠ same condition
CELSR1 p.Pro46His Uncertain significance ★★ ⚠ same condition
CELSR1 p.Ser2825Leu Uncertain significance ★★ same condition
CELSR1 p.Val2338Ile Uncertain significance ★★ ⚠ same condition
CELSR1 p.Leu979Phe Likely pathogenic ★ ⚠ same condition
CELSR1 p.Ala2486Pro Uncertain significance ★ same condition
CELSR1 p.Asp1201Asn Conflicting classifications of pathogenicity ★ same condition

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-ser533ile (accessed [today's date]).

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