# NM_000518.5(HBB):c.91A>C (p.Arg31=)

https://sugi.bio/variant/hbb-p-arg31

## Summary

**HBB p.Arg31= (c.91A>C)** is classified **Likely pathogenic** in HBB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-23). Absent from gnomAD v4.1; Associated with beta thalassemia.

**At a glance:** Likely pathogenic · review: Multiple submitters · rsID rs35684407 · 7 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the HBB gene that is considered likely disease-causing, submitted by 7 submitters, and is linked to beta thalassemia.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 106 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0000871/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [HBB](https://sugi.bio/atlas/gene/HBB/) |
| Protein change (HGVS p.) | p.Arg31= |
| Coding change (HGVS c.) | c.91A>C |
| MANE Select transcript | [NM_000518](https://www.ncbi.nlm.nih.gov/nuccore/NM_000518) |
| dbSNP | [rs35684407](https://www.ncbi.nlm.nih.gov/snp/rs35684407/) |
| Variant type | single nucleotide variant |
| Location | chr11:5226931-5226931 (GRCh38) |
| ClinVar | [VCV590773](https://www.ncbi.nlm.nih.gov/clinvar/variation/590773/) |

**All HGVS expressions:** `LRG_1232:g.5141A>C`, `LRG_1232t1:c.91A>C`, `NC_000011.10:g.5226931T>G`, `NC_000011.9:g.5248161T>G`, `NG_000007.3:g.70685A>C`, `NG_042296.1:g.462T>G`, `NG_046672.1:g.4866T>G`, `NG_059281.1:g.5141A>C`, `NM_000518.5:c.91A>C`

## Computational & population evidence {#evidence}

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

- **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 **donor gain** (Δ 0.41) — consistent with the pathogenic call
- Conservation: phyloP 4.818, GERP 1.87, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 22.7**. 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 **0.00**, donor loss **0.23**, acceptor gain **0.00**, donor gain **0.41**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.41**.
- Pangolin: Δ**0.47** (loss), gain 0.20 / loss 0.47. SpliceAI calls gain. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is 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}

**HBB** population constraint: LOEUF 1.964, pLI 7.4233e-10, missense-Z 0.77937. *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):

- **beta-thalassemia HBB/LCRB** — Definitive (AR)
- **hemoglobin M disease** — Definitive (AD)
- **obsolete sickle cell disease and related diseases** — Definitive (AR)
- **unstable hemoglobin disease** — Definitive (AD)

## Protein context {#protein}

Residue **31** lies in a UniProt-annotated variant site (in tacoma; unstable); a functional site ((microbial infection) cleavage; by n.americanus apr-2); an α-helix; the globin domain.

AlphaFold model confidence (whole protein): pLDDT 97.09, 97% of residues very-high.

**350 experimental structure(s)** (PDB): [1A00](https://www.rcsb.org/structure/1A00), [1A01](https://www.rcsb.org/structure/1A01), [1A0U](https://www.rcsb.org/structure/1A0U), [1A0Z](https://www.rcsb.org/structure/1A0Z), [1A3N](https://www.rcsb.org/structure/1A3N), [1A3O](https://www.rcsb.org/structure/1A3O) — incl. mutant structure 1A00.

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

*Describes the biological roles of HBB (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:** HBB's established molecular role includes oxygen binding. p.Arg31= falls in the globin domain. In Reactome, HBB is annotated in disease pathway(s) including **Heme assimilation**.

**Disease mechanism (Reactome):** HBB loss or alteration is curated in [Heme assimilation](https://reactome.org/content/detail/R-HSA-9927020).

### Pathways affected {#pathways}

HBB participates in **10 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Heme assimilation](https://reactome.org/content/detail/R-HSA-9927020) | curated |
| [Cytoprotection by HMOX1](https://reactome.org/content/detail/R-HSA-9707564) | curated |
| [Erythrocytes take up carbon dioxide and release oxygen](https://reactome.org/content/detail/R-HSA-1237044) | curated |
| [Erythrocytes take up oxygen and release carbon dioxide](https://reactome.org/content/detail/R-HSA-1247673) | curated |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [Heme signaling](https://reactome.org/content/detail/R-HSA-9707616) | curated |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | curated |
| [Scavenging of heme from plasma](https://reactome.org/content/detail/R-HSA-2168880) | curated |
| [Chaperone Mediated Autophagy](https://reactome.org/content/detail/R-HSA-9613829) | electronic |
| [Late endosomal microautophagy](https://reactome.org/content/detail/R-HSA-9615710) | electronic |

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

**Molecular function:** oxygen binding, hemoglobin binding.

**Biological process:** inflammatory response, oxygen transport, nitric oxide transport, response to hydrogen peroxide, hydrogen peroxide catabolic process, renal absorption.

## Clinical significance {#significance}

**Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-23.

**Submitter consensus:** conflicting (4 Likely pathogenic, 2 Pathogenic, 1 likely pathogenic).

**Submission history:** 7 submissions (2018–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| The ITHANET community portal, The Cyprus Institute of Neurology and Genetics | Pathogenic | no assertion criteria provided | curation | 2019-11-25 |
| Core Molecular Diagnostic Lab, McGill University Health Centre | Likely pathogenic | criteria provided, single submitter | clinical testing | 2018-08-30 |
| MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN | Pathogenic | no assertion criteria provided | clinical testing | 2024-05-07 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | likely pathogenic | criteria provided, single submitter | clinical testing | 2025-09-05 |
| Natera, Inc. | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-02-18 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-06-23 |
| Dasa | Likely pathogenic | criteria provided, single submitter | clinical testing | 2025-08-02 |

## Associated conditions {#conditions}

[beta thalassemia](https://sugi.bio/atlas/disease/beta-thalassemia/), [beta-thalassemia HBB/LCRB](https://sugi.bio/atlas/disease/beta-thalassemia-hbb-lcrb/).

**Reported phenotype names (ClinVar):** beta Thalassemia, not provided, Beta-thalassemia HBB/LCRB, none provided, Cooley's anemia, Erythroblastic anemia, Mediterranean anemia.

## Same-residue context {#hotspot}

Residue **31** carries **5 other pathogenic ClinVar variants** — a recurrently-mutated position: [HBB p.Arg31Thr](/variant/hbb-p-arg31thr), [HBB p.Arg31Met](/variant/hbb-p-arg31met), [HBB p.Arg31Gly](/variant/hbb-p-arg31gly), [HBB p.Arg31fs](/variant/hbb-p-arg31fs), [HBB p.Arg31dup](/variant/hbb-p-arg31dup). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related HBB variant pages (same residue, condition, or type): [HBB p.Arg31Gly](/variant/hbb-p-arg31gly), [HBB p.Arg31Thr](/variant/hbb-p-arg31thr), [HBB p.Arg31Ser](/variant/hbb-p-arg31ser), [HBB p.Arg31dup](/variant/hbb-p-arg31dup), [HBB p.Arg31fs](/variant/hbb-p-arg31fs), [HBB p.Arg31Met](/variant/hbb-p-arg31met), [HBB c.316-146T>G](/variant/hbb-c-316-minus-146t-g), [HBB c.316-197C>T](/variant/hbb-c-316-minus-197c-t).

### 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 590773). 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.*