Is CELSR3 p.Ala1959Thr (c.5875G>A) pathogenic?

CELSR3 p.Ala1959Thr (c.5875G>A) is classified Conflicting classifications of pathogenicity in CELSR3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-06-30). AlphaMissense: likely benign (0.149); Very rare (popmax 0.0078%, nfe); Associated with bladder exstrophy-epispadias-cloacal exstrophy complex.

What condition is associated with CELSR3 p.Ala1959Thr (c.5875G>A)?

CELSR3 p.Ala1959Thr (c.5875G>A) is associated with bladder exstrophy-epispadias-cloacal exstrophy complex (ClinVar).

How common is CELSR3 p.Ala1959Thr (c.5875G>A) in the general population?

CELSR3 p.Ala1959Thr (c.5875G>A) is very rare (popmax 0.0078%, nfe) (gnomAD).

What do computational predictors say about CELSR3 p.Ala1959Thr (c.5875G>A)?

AlphaMissense predicts likely benign (score 0.149) — an in-silico prediction, not a clinical call.

CELSR3 p.Ala1959Thr

c.5875G>A · rs139837673 · VCV3142105

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.149 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0078%, nfe)

Conditions

bladder exstrophy-epispadias-cloacal exstrophy complex

Computational evidence

Protein change
AlphaMissense	0.149	likely benign
REVEL	0.462	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP 1.2, phastCons 0.98
Regional constraint	o/e 0.69	unconstrained · MANE · 12 kb · p 9.5e-43 · regional, not allelic
Overall
CADD	22.1	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 0.0078% European (non-Finnish) · 92/1,179,492 alleles

Filtering AF 0.00648% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.006%

Overall 0.00627% 101/1,612,118 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0078%	12,821
Admixed American	0.00502%	19,925
Remaining individualsnot grpmax-eligible	0.00481%	20,801
African / African-American	0.00267%	37,427
Finnishnot grpmax-eligible	0.00158%	63,318

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.Ala1959Thr
Coding: c.5875G>A
MANE Select: NM_001407
dbSNP: rs139837673
Type: single nucleotide variant
Location: chr3:48651925 (GRCh38)
Gene constraint: LOEUF 0.344 · pLI 1.00 (gnomAD)
Residue 1959: the egf-like 5; calcium-binding domain; a disulfide bond

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

Disease context

bladder exstrophy-epispadias-cloacal exstrophy complex — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CELSR3 p.Arg3189Gln Benign/Likely benign ★★ same condition
CELSR3 p.Arg3033His Benign ★ same condition
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

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-ala1959thr (accessed [today's date]).

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