# NM_033377.2(CGB1):c.10A>C (p.Arg4=)

https://sugi.bio/variant/cgb1-p-arg4

## Summary

**CGB1 p.Arg4= (c.10A>C)** is classified **Likely benign** in CGB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). Ultra-rare (popmax 0.027%, amr).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.027%, amr)

## For patients & families {#patients}

This is a change in the CGB1 gene that is classified as likely benign — not considered disease-causing, 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 | [CGB1](https://sugi.bio/atlas/gene/CGB1/) |
| Protein change (HGVS p.) | p.Arg4= |
| Coding change (HGVS c.) | c.10A>C |
| MANE Select transcript | [NM_033377](https://www.ncbi.nlm.nih.gov/nuccore/NM_033377) |
| Variant type | single nucleotide variant |
| Location | chr19:49036303-49036303 (GRCh38) |
| ClinVar | [VCV4001911](https://www.ncbi.nlm.nih.gov/clinvar/variation/4001911/) |

**All HGVS expressions:** `NC_000019.10:g.49036303T>G`, `NC_000019.9:g.49539560T>G`, `NM_001382421.1:c.-27A>C`, `NM_033377.2:c.10A>C`

## 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 **acceptor loss** (Δ 0.44) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.488, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 14.68**. 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 **0.44**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.44**, donor loss **0.00**, acceptor gain **0.06**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.027%** (amr) · FAF95 0.0169% · FAF99 0.0138% · 16/59,194 in the highest group · 159/1,599,896 alleles overall — ultra-rare (popmax 0.027%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.027% | 3,700 |
| European (non-Finnish) | 0.0116% | 8,589 |
| Remaining individuals (not grpmax-eligible) | 0.00805% | 12,416 |
| African / African-American | 0.00135% | 74,182 |

*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}

**CGB1** population constraint: LOEUF 1.532, pLI 0.10728, missense-Z 0.69144. *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 74.53, 32% of residues very-high.

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

*Describes the biological roles of CGB1 (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:** CGB1's established molecular role includes hormone activity.


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

**Molecular function:** hormone activity.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-11.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-11 |

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

## Similar variants {#similar}

Related CGB1 variant pages (same residue, condition, or type): [CGB1 p.Ala103Ser](/variant/cgb1-p-ala103ser), [CGB1 p.Ala141Val](/variant/cgb1-p-ala141val), [CGB1 p.Ala18Thr](/variant/cgb1-p-ala18thr), [CGB1 p.Ala35Val](/variant/cgb1-p-ala35val), [CGB1 p.Arg113His](/variant/cgb1-p-arg113his), [CGB1 p.Arg151His](/variant/cgb1-p-arg151his), [CGB1 p.Arg151Leu](/variant/cgb1-p-arg151leu), [CGB1 p.Arg151Pro](/variant/cgb1-p-arg151pro).

### 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 4001911). 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.*