Is CELSR2 p.Pro1750Ser (c.5248C>T) pathogenic?

CELSR2 p.Pro1750Ser (c.5248C>T) is classified Likely benign in CELSR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-04-01). AlphaMissense: likely benign (0.0724); Very rare (popmax 0.00223%, eas); Associated with CELSR2-related disorder.

What condition is associated with CELSR2 p.Pro1750Ser (c.5248C>T)?

CELSR2 p.Pro1750Ser (c.5248C>T) is associated with CELSR2-related disorder (ClinVar).

How common is CELSR2 p.Pro1750Ser (c.5248C>T) in the general population?

CELSR2 p.Pro1750Ser (c.5248C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about CELSR2 p.Pro1750Ser (c.5248C>T)?

AlphaMissense predicts likely benign (score 0.0724) — an in-silico prediction, not a clinical call.

CELSR2 p.Pro1750Ser

c.5248C>T · rs199761472 · VCV3054507

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0724 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

CELSR2-related disorder

Computational evidence

Protein change
AlphaMissense	0.0724	likely benign
REVEL	0.212	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP -0.41, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 15 kb · p 2.9e-09 · regional, not allelic
Overall
CADD	14.45	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 0.00223% East Asian · 1/44,828 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.00496% 80/1,612,690 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.199%	502
Remaining individualsnot grpmax-eligible	0.0128%	7,805
East Asiangrpmax	0.00223%	44,828
European (non-Finnish)	0.00102%	98,251

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1750Ser
Coding: c.5248C>T
MANE Select: NM_001408
dbSNP: rs199761472
Type: single nucleotide variant
Location: chr1:109264324 (GRCh38)
Gene constraint: LOEUF 0.396 · pLI 1.00 (gnomAD)
Residue 1750: the laminin g-like 2 domain

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

Disease context

CELSR2-related disorder

Similar variants

CELSR2 p.Arg426Ter Uncertain significance same condition
CELSR2 p.Arg881Ter Uncertain significance same condition
CELSR2 p.Ala2579= Likely benign same condition
CELSR2 p.Arg2015= Benign same condition
CELSR2 p.Arg2191His Likely benign same condition
CELSR2 p.Asn1182= Likely benign same condition
CELSR2 p.Asn1830= Likely benign same condition
CELSR2 p.Gln2053= Likely benign 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/celsr2-p-pro1750ser (accessed [today's date]).

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