# NM_001408.3(CELSR2):c.6750C>A (p.Ile2250=)

https://sugi.bio/variant/celsr2-p-ile2250

## Summary

**CELSR2 p.Ile2250= (c.6750C>A)** is classified **Likely benign** in CELSR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-16). Very rare (popmax 0.000509%, nfe); Associated with CELSR2-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs745890195 · 1 submitter · 1 linked condition · very rare (popmax 0.000509%, nfe)

## For patients & families {#patients}

This is a change in the CELSR2 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to CELSR2-related disorder.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CELSR2](https://sugi.bio/atlas/gene/CELSR2/) |
| Protein change (HGVS p.) | p.Ile2250= |
| Coding change (HGVS c.) | c.6750C>A |
| MANE Select transcript | [NM_001408](https://www.ncbi.nlm.nih.gov/nuccore/NM_001408) |
| dbSNP | [rs745890195](https://www.ncbi.nlm.nih.gov/snp/rs745890195/) |
| Variant type | single nucleotide variant |
| Location | chr1:109269228-109269228 (GRCh38) |
| ClinVar | [VCV3041783](https://www.ncbi.nlm.nih.gov/clinvar/variation/3041783/) |

**All HGVS expressions:** `NC_000001.10:g.109811850C>A`, `NC_000001.11:g.109269228C>A`, `NG_052669.1:g.24524C>A`, `NM_001408.3:c.6750C>A`

## Computational & population evidence {#evidence}

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

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 2.706, GERP 1.69, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.36**. 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.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.20**. Largest is donor gain, 23 bp away.
  These are **raw** scores. Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — can legitimately show 0 where this shows a score; the masked figures are not available for this record.
- Population frequency (gnomAD v4.1): grpmax **0.000509%** (nfe) · FAF95 0.000183% · FAF99 0.00012% · 6/1,179,918 in the highest group · 6/1,612,816 alleles overall — very rare (popmax 0.000509%, nfe).

*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}

**CELSR2** population constraint: LOEUF 0.396, pLI 1, missense-Z 3.9105. *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 **2250** lies in the gain-b domain.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-05-16.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-05-16 |

## Associated conditions {#conditions}

[CELSR2-related disorder](https://sugi.bio/atlas/disease/celsr2-related-disorder/).

**Reported phenotype names (ClinVar):** CELSR2-related disorder, CELSR2-related condition.

## Similar variants {#similar}

Related CELSR2 variant pages (same residue, condition, or type): [CELSR2 p.Arg426Ter](/variant/celsr2-p-arg426ter), [CELSR2 p.Arg881Ter](/variant/celsr2-p-arg881ter), [CELSR2 p.Ala2579=](/variant/celsr2-p-ala2579), [CELSR2 p.Arg2015=](/variant/celsr2-p-arg2015), [CELSR2 p.Arg2191His](/variant/celsr2-p-arg2191his), [CELSR2 p.Asn1182=](/variant/celsr2-p-asn1182), [CELSR2 p.Asn1830=](/variant/celsr2-p-asn1830), [CELSR2 p.Gln2053=](/variant/celsr2-p-gln2053).

### 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 3041783). 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.*