# NM_152311.5(CLRN3):c.233T>C (p.Leu78Ser)

https://sugi.bio/variant/clrn3-p-leu78ser

## Summary

**CLRN3 p.Leu78Ser (c.233T>C)** is classified **Uncertain significance** in CLRN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-09). AlphaMissense: likely benign (0.2058); Very rare (popmax 0.000169%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · rsID rs755477937 · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.000169%, nfe)

## For patients & families {#patients}

This is a change in the CLRN3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter.

*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 | [CLRN3](https://sugi.bio/atlas/gene/CLRN3/) |
| Protein change (HGVS p.) | p.Leu78Ser |
| Coding change (HGVS c.) | c.233T>C |
| MANE Select transcript | [NM_152311](https://www.ncbi.nlm.nih.gov/nuccore/NM_152311) |
| dbSNP | [rs755477937](https://www.ncbi.nlm.nih.gov/snp/rs755477937/) |
| Variant type | single nucleotide variant |
| Location | chr10:127883872-127883872 (GRCh38) |
| ClinVar | [VCV2210522](https://www.ncbi.nlm.nih.gov/clinvar/variation/2210522/) |

**All HGVS expressions:** `NC_000010.10:g.129682136A>G`, `NC_000010.11:g.127883872A>G`, `NM_152311.5:c.233T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.2058)
- REVEL 0.268 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.965 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor gain** (Δ 0.27) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.708, GERP 2.32, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 24.0**. 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 1.08** across the covering region of the MANE Select transcript (127,878,152–127,892,784), spanning 14,632 bp. Chi-square p 0.19. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.01**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.27**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.000169%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,954 in the highest group · 2/1,461,790 alleles overall — very rare (popmax 0.000169%, 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}

**CLRN3** population constraint: LOEUF 1.166, pLI 0.0059258, missense-Z -0.057882. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 86.68, 53% of residues very-high.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-07-09.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-07-09 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related CLRN3 variant pages (same residue, condition, or type): [CLRN3 p.Ala149Glu](/variant/clrn3-p-ala149glu), [CLRN3 p.Ala149Ser](/variant/clrn3-p-ala149ser), [CLRN3 p.Ala149Thr](/variant/clrn3-p-ala149thr), [CLRN3 p.Ala149Val](/variant/clrn3-p-ala149val), [CLRN3 p.Arg208Trp](/variant/clrn3-p-arg208trp), [CLRN3 p.Asn46His](/variant/clrn3-p-asn46his), [CLRN3 p.Gln207Arg](/variant/clrn3-p-gln207arg), [CLRN3 p.Gln31Pro](/variant/clrn3-p-gln31pro).

### 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 2210522). 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.*