# NM_000518.5(HBB):c.128T>C (p.Phe43Ser)

https://sugi.bio/variant/hbb-p-phe43ser

## Summary

**HBB p.Phe43Ser (c.128T>C)** is classified **Pathogenic** in HBB (ClinVar, Multiple submitters, 4 submitters; last evaluated 2022-03-25). AlphaMissense: likely pathogenic (0.9936); Absent from gnomAD v4.1; Associated with Heinz body anemia.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs34378160 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the HBB gene that is considered disease-causing, submitted by 4 submitters, and is linked to Heinz body anemia.

*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.*

|  |  |
| --- | --- |
| Diagnostic panels | HBB is a diagnostic-grade gene on 4 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010718/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.Phe43Ser |
| Coding change (HGVS c.) | c.128T>C |
| MANE Select transcript | [NM_000518](https://www.ncbi.nlm.nih.gov/nuccore/NM_000518) |
| dbSNP | [rs34378160](https://www.ncbi.nlm.nih.gov/snp/rs34378160/) |
| Variant type | single nucleotide variant |
| Location | chr11:5226764-5226764 (GRCh38) |
| ClinVar | [VCV15190](https://www.ncbi.nlm.nih.gov/clinvar/variation/15190/) |

**All HGVS expressions:** `LRG_1232:g.5308T>C`, `LRG_1232t1:c.128T>C`, `NC_000011.10:g.5226764A>G`, `NC_000011.9:g.5247994A>G`, `NG_000007.3:g.70852T>C`, `NG_042296.1:g.295A>G`, `NG_046672.1:g.4699A>G`, `NG_059281.1:g.5308T>C`, `NM_000518.5:c.128T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9936) — concordant with the pathogenic call
- REVEL 0.978 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.625 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 10.696, GERP 1.87, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 3%** most-pathogenic-predicted substitutions in HBB (of 861 modeled).
- CADD: **PHRED 26.3**. 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 0.88** across the covering region of the MANE Select transcript (5,225,601–5,227,021), spanning 1,420 bp. Chi-square p 0.11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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 **43** lies in a UniProt-annotated variant site (in louisville; unstable); a UniProt-annotated variant site (in hammersmith); a UniProt-annotated variant site (in bruxelles); 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.Phe43Ser 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}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-03-25.

**Submitter consensus:** conflicting (4 Pathogenic, 2 other).

**Submission history:** 6 submissions (1988–2022); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2017-12-15 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2022-03-25 |
| OMIM | other | no assertion criteria provided | literature only | 1988-06-01 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 1988-06-01 |
| Natera, Inc. | Pathogenic | no assertion criteria provided | clinical testing | 2017-03-17 |

## Associated conditions {#conditions}

[Heinz body anemia](https://sugi.bio/atlas/disease/heinz-body-anemia/), [beta thalassemia](https://sugi.bio/atlas/disease/beta-thalassemia/).

**Reported phenotype names (ClinVar):** HEMOGLOBIN HAMMERSMITH, HEMOGLOBIN CHIBA, Heinz body anemia, not provided, beta Thalassemia, none provided, Heinz body hemolytic anemia, Cooley's anemia, Erythroblastic anemia, Mediterranean anemia.

## Same-residue context {#hotspot}

Residue **43** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [HBB p.Phe43fs](/variant/hbb-p-phe43fs), [HBB p.Phe43Leu](/variant/hbb-p-phe43leu), [HBB p.Phe43Val](/variant/hbb-p-phe43val), [HBB p.Phe43Ile](/variant/hbb-p-phe43ile). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related HBB variant pages (same residue, condition, or type): [HBB p.Phe43Leu](/variant/hbb-p-phe43leu), [HBB p.Phe43Ile](/variant/hbb-p-phe43ile), [HBB p.Phe43del](/variant/hbb-p-phe43del), [HBB p.Phe43Val](/variant/hbb-p-phe43val), [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).

### 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 15190). 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.*