# NM_001408.3(CELSR2):c.3546C>T (p.Asn1182=)

https://sugi.bio/variant/celsr2-p-asn1182

## Summary

**CELSR2 p.Asn1182= (c.3546C>T)** is classified **Likely benign** in CELSR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-06-19). Ultra-rare (popmax 0.0805%, eas); Associated with CELSR2-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs183828529 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0805%, eas)

## 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.Asn1182= |
| Coding change (HGVS c.) | c.3546C>T |
| MANE Select transcript | [NM_001408](https://www.ncbi.nlm.nih.gov/nuccore/NM_001408) |
| dbSNP | [rs183828529](https://www.ncbi.nlm.nih.gov/snp/rs183828529/) |
| Variant type | single nucleotide variant |
| Location | chr1:109258667-109258667 (GRCh38) |
| ClinVar | [VCV3033110](https://www.ncbi.nlm.nih.gov/clinvar/variation/3033110/) |

**All HGVS expressions:** `NC_000001.10:g.109801289C>T`, `NC_000001.11:g.109258667C>T`, `NG_052669.1:g.13963C>T`, `NM_001408.3:c.3546C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -2.435, GERP -1.32 — fast-evolving / accelerated position
- CADD: **PHRED 8.414**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.87 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0805%** (eas) · FAF95 0.0589% · FAF99 0.0515% · 33/40,990 in the highest group · 52/1,548,704 alleles overall — ultra-rare (popmax 0.0805%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0805% | 1,242 |
| Admixed American | 0.00786% | 12,719 |
| African / African-American | 0.00684% | 14,628 |
| Remaining individuals (not grpmax-eligible) | 0.00167% | 60,008 |
| South Asian | 0.00119% | 84,292 |
| European (non-Finnish) | 0.000698% | 143,183 |

*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.*

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-06-19.

**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 | 2019-06-19 |

## 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.Asn1830=](/variant/celsr2-p-asn1830), [CELSR2 p.Gln2053=](/variant/celsr2-p-gln2053), [CELSR2 p.Ile2250=](/variant/celsr2-p-ile2250).

### 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 3033110). 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.*