# NM_001407.3(CELSR3):c.6342C>T (p.Phe2114=)

https://sugi.bio/variant/celsr3-p-phe2114

## Summary

**CELSR3 p.Phe2114= (c.6342C>T)** is classified **Likely benign** in CELSR3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-09). Very rare (popmax 0.00167%, amr); Associated with CELSR3-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs868152619 · 1 submitter · 1 linked condition · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the CELSR3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to CELSR3-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 | [CELSR3](https://sugi.bio/atlas/gene/CELSR3/) |
| Protein change (HGVS p.) | p.Phe2114= |
| Coding change (HGVS c.) | c.6342C>T |
| MANE Select transcript | [NM_001407](https://www.ncbi.nlm.nih.gov/nuccore/NM_001407) |
| dbSNP | [rs868152619](https://www.ncbi.nlm.nih.gov/snp/rs868152619/) |
| Variant type | single nucleotide variant |
| Location | chr3:48650920-48650920 (GRCh38) |
| ClinVar | [VCV3050563](https://www.ncbi.nlm.nih.gov/clinvar/variation/3050563/) |

**All HGVS expressions:** `NC_000003.11:g.48688353G>A`, `NC_000003.12:g.48650920G>A`, `NG_034061.1:g.16996C>T`, `NM_001407.3:c.6342C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.21) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 0.188, GERP -4.72, phastCons 0.248 — weakly conserved position
- CADD: **PHRED 7.088**. 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 **0.01**, donor loss **0.21**, acceptor gain **0.03**, donor gain **0.00**. Largest is donor loss, 28 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/59,996 in the highest group · 3/1,611,178 alleles overall — very rare (popmax 0.00167%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00167% | 59,996 |
| South Asian | 0.0011% | 90,998 |
| European (non-Finnish) | 8.48e-05% | 1,179,814 |

*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 **2114** lies in the laminin egf-like domain.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-07-09.

**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 | 2019-07-09 |

## Associated conditions {#conditions}

[CELSR3-related disorder](https://sugi.bio/atlas/disease/celsr3-related-disorder/).

**Reported phenotype names (ClinVar):** CELSR3-related disorder, CELSR3-related condition.

## Similar variants {#similar}

Related CELSR3 variant pages (same residue, condition, or type): [CELSR3 p.Phe282Ser](/variant/celsr3-p-phe282ser), [CELSR3 p.Cys1502Tyr](/variant/celsr3-p-cys1502tyr), [CELSR3 p.Ala3148Glu](/variant/celsr3-p-ala3148glu), [CELSR3 c.7464-9T>C](/variant/celsr3-c-7464-minus-9t-c), [CELSR3 c.8086-5T>G](/variant/celsr3-c-8086-minus-5t-g), [CELSR3 c.8165+7T>C](/variant/celsr3-c-8165-plus-7t-c), [CELSR3 c.9912-8G>A](/variant/celsr3-c-9912-minus-8g-a), [CELSR3 c.*9C>T](/variant/celsr3-c-star-9c-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 2026-10-14); 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 3050563). 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.*