# NM_001378328.1(CELSR1):c.8232C>T (p.Phe2744=)

https://sugi.bio/variant/celsr1-p-phe2744

## Summary

**CELSR1 p.Phe2744= (c.8232C>T)** is classified **Likely benign** in CELSR1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-02). Very rare (popmax 0.0096%, afr); Associated with CELSR1-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · 1 submitter · 1 linked condition · very rare (popmax 0.0096%, afr)

## For patients & families {#patients}

This is a change in the CELSR1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to CELSR1-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 | [CELSR1](https://sugi.bio/atlas/gene/CELSR1/) |
| Protein change (HGVS p.) | p.Phe2744= |
| Coding change (HGVS c.) | c.8232C>T |
| MANE Select transcript | [NM_001378328](https://www.ncbi.nlm.nih.gov/nuccore/NM_001378328) |
| Variant type | single nucleotide variant |
| Location | chr22:46366454-46366454 (GRCh38) |
| ClinVar | [VCV3352777](https://www.ncbi.nlm.nih.gov/clinvar/variation/3352777/) |

**All HGVS expressions:** `NC_000022.10:g.46762351G>A`, `NC_000022.11:g.46366454G>A`, `NG_030466.2:g.175717C>T`, `NM_001378328.1:c.8232C>T`, `NM_014246.4:c.8232C>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 1.272, GERP 0.301, phastCons 0.001 — weakly conserved position
- CADD: **PHRED 6.899**. 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 (G>T, Δ0.55 acceptor 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 **0.0096%** (afr) · FAF95 0.00468% · FAF99 0.00345% · 7/72,928 in the highest group · 34/1,550,290 alleles overall — very rare (popmax 0.0096%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0096% | 10,418 |
| South Asian | 0.00952% | 10,509 |
| Finnish (not grpmax-eligible) | 0.00339% | 29,516 |
| European (non-Finnish) | 0.00148% | 67,456 |

*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}

**CELSR1** population constraint: LOEUF 0.564, pLI 3.7951e-10, missense-Z 0.63145. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **epilepsy** — Refuted (AR)

## Protein context {#protein}

Residue **2744** lies in a UniProt-annotated variant site (in lmphm9).

**2 experimental structure(s)** (PDB): [7SZ8](https://www.rcsb.org/structure/7SZ8), [8D40](https://www.rcsb.org/structure/8D40).

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2019-04-02.

**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 | 2019-04-02 |

## Associated conditions {#conditions}

[CELSR1-related disorder](https://sugi.bio/atlas/disease/celsr1-related-disorder/).

**Reported phenotype names (ClinVar):** CELSR1-related disorder, CELSR1-related condition.

## Similar variants {#similar}

Related CELSR1 variant pages (same residue, condition, or type): [CELSR1 p.Phe2744Leu](/variant/celsr1-p-phe2744leu), [CELSR1 p.Arg1643Gln](/variant/celsr1-p-arg1643gln), [CELSR1 p.Pro46His](/variant/celsr1-p-pro46his), [CELSR1 p.Ser2825Leu](/variant/celsr1-p-ser2825leu), [CELSR1 p.Val2338Ile](/variant/celsr1-p-val2338ile), [CELSR1 p.Leu979Phe](/variant/celsr1-p-leu979phe), [CELSR1 p.Ala2486Pro](/variant/celsr1-p-ala2486pro), [CELSR1 p.Asp1201Asn](/variant/celsr1-p-asp1201asn).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3352777). 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.*