Is CELSR2 p.Ser1503Tyr (c.4508C>A) pathogenic?

CELSR2 p.Ser1503Tyr (c.4508C>A) is classified Uncertain significance in CELSR2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-19). AlphaMissense: likely pathogenic (0.6135); Ultra-rare (popmax 0.0749%, nfe).

How common is CELSR2 p.Ser1503Tyr (c.4508C>A) in the general population?

CELSR2 p.Ser1503Tyr (c.4508C>A) is ultra-rare (popmax 0.0749%, nfe) (gnomAD).

What do computational predictors say about CELSR2 p.Ser1503Tyr (c.4508C>A)?

AlphaMissense predicts likely pathogenic (score 0.6135) — an in-silico prediction, not a clinical call.

CELSR2 p.Ser1503Tyr

c.4508C>A · rs145591944 · VCV2346803

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6135 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0749%, nfe)

Computational evidence

Protein change
AlphaMissense	0.6135	likely pathogenic
REVEL	0.558	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	25.4	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 0.0749% European (non-Finnish) · 884/1,180,042 alleles

Filtering AF 0.0708% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0691%

Overall 0.0605% 977/1,614,014 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0749%	1,335
Finnishnot grpmax-eligible	0.0688%	1,454
Remaining individualsnot grpmax-eligible	0.0416%	2,403
Admixed American	0.0167%	6,001
Middle Eastern	0.0164%	6,080
African / African-American	0.0133%	7,492
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,608
South Asian	0.0011%	91,080

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.Ser1503Tyr
Coding: c.4508C>A
MANE Select: NM_001408
dbSNP: rs145591944
Type: single nucleotide variant
Location: chr1:109262408 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 1503: the laminin g-like 1 domain

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

Similar variants

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
CELSR2 p.Arg1978Gln 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-ser1503tyr (accessed [today's date]).

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