# NM_001407.3(CELSR3):c.5875G>A (p.Ala1959Thr)

https://sugi.bio/variant/celsr3-p-ala1959thr

## Summary

**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.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs139837673 · 2 submitters · 1 linked condition · AlphaMissense likely benign · very rare (popmax 0.0078%, nfe)

## For patients & families {#patients}

This is a change in the CELSR3 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to bladder exstrophy-epispadias-cloacal exstrophy complex.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026333/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CELSR3](https://sugi.bio/atlas/gene/CELSR3/) |
| Protein change (HGVS p.) | p.Ala1959Thr |
| Coding change (HGVS c.) | c.5875G>A |
| MANE Select transcript | [NM_001407](https://www.ncbi.nlm.nih.gov/nuccore/NM_001407) |
| dbSNP | [rs139837673](https://www.ncbi.nlm.nih.gov/snp/rs139837673/) |
| Variant type | single nucleotide variant |
| Location | chr3:48651925-48651925 (GRCh38) |
| ClinVar | [VCV3142105](https://www.ncbi.nlm.nih.gov/clinvar/variation/3142105/) |

**All HGVS expressions:** `NC_000003.11:g.48689358C>T`, `NC_000003.12:g.48651925C>T`, `NG_034061.1:g.15991G>A`, `NM_001407.3:c.5875G>A`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.149)
- REVEL 0.462 (indeterminate)
- Conservation: phyloP 2.191, GERP 1.19, phastCons 0.976 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.1**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.69** across the covering region of the MANE Select transcript (48,648,291–48,659,962), spanning 11,671 bp. Chi-square p 9.5e-43. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.0078%** (nfe) · FAF95 0.00648% · FAF99 0.006% · 92/1,179,492 in the highest group · 101/1,612,118 alleles overall — very rare (popmax 0.0078%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.0078% | 12,821 |
| Admixed American | 0.00502% | 19,925 |
| Remaining individuals (not grpmax-eligible) | 0.00481% | 20,801 |
| African / African-American | 0.00267% | 37,427 |
| Finnish (not grpmax-eligible) | 0.00158% | 63,318 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CELSR3** population constraint: LOEUF 0.344, pLI 1, missense-Z 5.1027. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **1959** lies in the egf-like 5; calcium-binding domain; a disulfide bond.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-06-30.

**Submitter consensus:** conflicting (1 Likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Obstetrics and Gynecology Department, Johns Hopkins School Of Medicine | Likely benign | criteria provided, single submitter | research |  |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-30 |

## Associated conditions {#conditions}

[bladder exstrophy-epispadias-cloacal exstrophy complex](https://sugi.bio/atlas/disease/bladder-exstrophy-epispadias-cloacal-exstrophy-complex/).

**Reported phenotype names (ClinVar):** Bladder exstrophy-epispadias-cloacal exstrophy complex, not specified, Bladder exstrophy-epispadias-cloacal extrophy complex, Exstrophy of the bladder-epispadias, Bladder exstrophy and epispadias complex, AllHighlyPenetrant.

## Similar variants {#similar}

Related CELSR3 variant pages (same residue, condition, or type): [CELSR3 p.Arg3189Gln](/variant/celsr3-p-arg3189gln), [CELSR3 p.Arg3033His](/variant/celsr3-p-arg3033his), [CELSR3 p.Ala2862Val](/variant/celsr3-p-ala2862val), [CELSR3 p.Arg2345His](/variant/celsr3-p-arg2345his), [CELSR3 p.Gly2265Ser](/variant/celsr3-p-gly2265ser), [CELSR3 p.Phe282Ser](/variant/celsr3-p-phe282ser), [CELSR3 p.Val1107Met](/variant/celsr3-p-val1107met), [CELSR3 p.Arg2886=](/variant/celsr3-p-arg2886).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); gnomAD v4.1 (Broad Institute, built 2026-10-06); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-07-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3142105). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*