# NM_004183.4(BEST1):c.916G>C (p.Glu306Gln)

https://sugi.bio/variant/best1-p-glu306gln

## Summary

**BEST1 p.Glu306Gln (c.916G>C)** is classified **Pathogenic** in BEST1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-17). AlphaMissense: likely pathogenic (0.8244); Absent from gnomAD v4.1.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2134453498 · 1 submitter · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BEST1 gene that is reported as disease-causing, but on limited review, 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 | [BEST1](https://sugi.bio/atlas/gene/BEST1/) |
| Protein change (HGVS p.) | p.Glu306Gln |
| Coding change (HGVS c.) | c.916G>C |
| MANE Select transcript | [NM_004183](https://www.ncbi.nlm.nih.gov/nuccore/NM_004183) |
| dbSNP | [rs2134453498](https://www.ncbi.nlm.nih.gov/snp/rs2134453498/) |
| Variant type | single nucleotide variant |
| Location | chr11:61959546-61959546 (GRCh38) |
| ClinVar | [VCV1482656](https://www.ncbi.nlm.nih.gov/clinvar/variation/1482656/) |

**All HGVS expressions:** `NC_000011.10:g.61959546G>C`, `NC_000011.9:g.61727018G>C`, `NG_009033.1:g.14663G>C`, `NM_001139443.3:c.736G>C`, `NM_001300786.2:c.688-346G>C`, `NM_001300787.2:c.736G>C`, `NM_001363591.3:c.598G>C`, `NM_001363592.2:c.1119G>C`, `NM_001363593.3:c.-57G>C`, `NM_004183.4:c.916G>C`, `NR_134580.2:n.1232G>C`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.8244) — concordant with the pathogenic call
- REVEL 0.966 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.762 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 9.578, GERP 2.25, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.2**. 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 0.91** across the covering region of the MANE Select transcript (61,951,807–61,964,119), spanning 12,312 bp. Chi-square p 0.011. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.20 donor loss), 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**BEST1** population constraint: LOEUF 1.28, pLI 3.209e-19, missense-Z 0.89191. *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):

- **BEST1-related dominant retinopathy** — Definitive (AD)

## Protein context {#protein}

Residue **306** lies in a UniProt-annotated variant site (in vmd2).

AlphaFold model confidence (whole protein): pLDDT 72.46, 55% of residues very-high.

**19 experimental structure(s)** (PDB): [8D1I](https://www.rcsb.org/structure/8D1I), [8D1J](https://www.rcsb.org/structure/8D1J), [8D1K](https://www.rcsb.org/structure/8D1K), [8D1L](https://www.rcsb.org/structure/8D1L), [8D1M](https://www.rcsb.org/structure/8D1M), [8D1O](https://www.rcsb.org/structure/8D1O).

## What this gene does {#gene-function}

*Describes the biological roles of BEST1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** BEST1's established molecular role includes intracellularly calcium-gated chloride channel activity.


### Pathways affected {#pathways}

BEST1 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Stimuli-sensing channels](https://reactome.org/content/detail/R-HSA-2672351) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** intracellularly calcium-gated chloride channel activity, chloride channel activity, identical protein binding, bicarbonate channel activity.

**Biological process:** chloride transport, transepithelial chloride transport, protein complex oligomerization.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-08-17.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-17 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Same-residue context {#hotspot}

Residue **306** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BEST1 p.Glu306Asp](/variant/best1-p-glu306asp), [BEST1 p.Glu306Gly](/variant/best1-p-glu306gly). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BEST1 variant pages (same residue, condition, or type): [BEST1 p.Glu306Asp](/variant/best1-p-glu306asp), [BEST1 p.Glu306Gly](/variant/best1-p-glu306gly), [BEST1 c.1100+1G>C](/variant/best1-c-1100-plus-1g-c), [BEST1 c.1101-1G>C](/variant/best1-c-1101-minus-1g-c), [BEST1 c.636+1G>A](/variant/best1-c-636-plus-1g-a), [BEST1 c.867+97G>A](/variant/best1-c-867-plus-97g-a), [BEST1 p.Ala10Thr](/variant/best1-p-ala10thr), [BEST1 p.Ala10Val](/variant/best1-p-ala10val).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1482656). 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.*