# NM_001906.6(CTRB1):c.392G>A (p.Arg131His)

https://sugi.bio/variant/ctrb1-p-arg131his

## Summary

**CTRB1 p.Arg131His (c.392G>A)** is classified **Uncertain significance** in CTRB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0834); Very rare (popmax 0.00372%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · very rare (popmax 0.00372%, nfe)

## For patients & families {#patients}

This is a change in the CTRB1 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 | [CTRB1](https://sugi.bio/atlas/gene/CTRB1/) |
| Protein change (HGVS p.) | p.Arg131His |
| Coding change (HGVS c.) | c.392G>A |
| MANE Select transcript | [NM_001906](https://www.ncbi.nlm.nih.gov/nuccore/NM_001906) |
| Variant type | single nucleotide variant |
| Location | chr16:75223524-75223524 (GRCh38) |
| ClinVar | [VCV4235781](https://www.ncbi.nlm.nih.gov/clinvar/variation/4235781/) |

**All HGVS expressions:** `NC_000016.10:g.75223524G>A`, `NC_000016.9:g.75257422G>A`, `NG_051057.1:g.9539G>A`, `NM_001329190.2:c.392G>A`, `NM_001906.6:c.392G>A`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0834)
- REVEL 0.247 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.21 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -4.226, GERP -4.39 — fast-evolving / accelerated position
- CADD: **PHRED 8.892**. 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 0.13** across the covering region of the MANE Select transcript (75,222,969–75,224,058), spanning 1,089 bp — the region is depleted of missense variation. Chi-square p 5.9e-17. 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, Δ0.38 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 **0.00372%** (nfe) · FAF95 0.0023% · FAF99 0.00188% · 16/429,626 in the highest group · 18/688,528 alleles overall — very rare (popmax 0.00372%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00372% | 26,852 |
| Remaining individuals (not grpmax-eligible) | 0.00314% | 31,890 |
| South Asian | 0.00177% | 56,546 |

*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}

**CTRB1** population constraint: LOEUF 1.902, pLI 4.6278e-05, missense-Z -1.4694. *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 **131** lies in the peptidase s1 domain.

AlphaFold model confidence (whole protein): pLDDT 91.90, 82% of residues very-high.

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

*Describes the biological roles of CTRB1 (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.*


### Pathways affected {#pathways}

CTRB1 participates in **2 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Activation of Matrix Metalloproteinases](https://reactome.org/content/detail/R-HSA-1592389) | curated |
| [Uptake of dietary cobalamins into enterocytes](https://reactome.org/content/detail/R-HSA-9758881) | curated |

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-31.

**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 | 2025-08-31 |

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

## Similar variants {#similar}

Related CTRB1 variant pages (same residue, condition, or type): [CTRB1 p.Arg131Cys](/variant/ctrb1-p-arg131cys), [CTRB1 p.Ala104Asp](/variant/ctrb1-p-ala104asp), [CTRB1 p.Ala138Thr](/variant/ctrb1-p-ala138thr), [CTRB1 p.Ala144Thr](/variant/ctrb1-p-ala144thr), [CTRB1 p.Ala150Ser](/variant/ctrb1-p-ala150ser), [CTRB1 p.Ala177Val](/variant/ctrb1-p-ala177val), [CTRB1 p.Ala261Val](/variant/ctrb1-p-ala261val), [CTRB1 p.Ala40Thr](/variant/ctrb1-p-ala40thr).

### 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 2026-10-14); 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 4235781). 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.*