# NM_000518.5(HBB):c.57G>A (p.Val19=)

https://sugi.bio/variant/hbb-p-val19

## Summary

**HBB p.Val19= (c.57G>A)** is classified **Conflicting classifications of pathogenicity** in HBB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2019-08-28). Absent from gnomAD v4.1.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1554918177 · 2 submitters · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the HBB gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters.

*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 | [HBB](https://sugi.bio/atlas/gene/HBB/) |
| Protein change (HGVS p.) | p.Val19= |
| Coding change (HGVS c.) | c.57G>A |
| MANE Select transcript | [NM_000518](https://www.ncbi.nlm.nih.gov/nuccore/NM_000518) |
| dbSNP | [rs1554918177](https://www.ncbi.nlm.nih.gov/snp/rs1554918177/) |
| Variant type | single nucleotide variant |
| Location | chr11:5226965-5226965 (GRCh38) |
| ClinVar | [VCV496001](https://www.ncbi.nlm.nih.gov/clinvar/variation/496001/) |

**All HGVS expressions:** `LRG_1232:g.5107G>A`, `LRG_1232t1:c.57G>A`, `NC_000011.10:g.5226965C>T`, `NC_000011.9:g.5248195C>T`, `NG_000007.3:g.70651G>A`, `NG_042296.1:g.496C>T`, `NG_046672.1:g.4900C>T`, `NG_059281.1:g.5107G>A`, `NM_000518.5:c.57G>A`

## 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 **donor gain** (Δ 0.71) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP -0.222, GERP -1.15 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 19.31**. 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 **0.14**, acceptor gain **0.00**, donor gain **0.71**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.71**.
- Pangolin: Δ**0.39** (loss), gain 0.33 / loss 0.39. 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 **19** lies in the globin domain; a UniProt-annotated variant site (in baden; slightly unstable).

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.Val19= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2019-08-28.

**Submitter consensus:** conflicting (1 Likely benign, 1 Uncertain significance).

**Submission history:** 2 submissions (2019); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-08-28 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-02-21 |

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

## Similar variants {#similar}

Related HBB variant pages (same residue, condition, or type): [HBB p.Val19Gly](/variant/hbb-p-val19gly), [HBB c.316-146T>G](/variant/hbb-c-316-minus-146t-g), [HBB c.316-197C>T](/variant/hbb-c-316-minus-197c-t), [HBB c.92+5G>C](/variant/hbb-c-92-plus-5g-c), [HBB c.-78A>C](/variant/hbb-c-minus-78a-c), [HBB c.*111A>G](/variant/hbb-c-star-111a-g), [HBB p.Ala28Ser](/variant/hbb-p-ala28ser), [HBB p.Lys18Ter](/variant/hbb-p-lys18ter).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 496001). 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.*