# NM_000190.4(HMBS):c.66C>T (p.Arg22=)

https://sugi.bio/variant/hmbs-p-arg22

## Summary

**HMBS p.Arg22= (c.66C>T)** is classified **Benign** in HMBS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-23). Ultra-rare (popmax 0.075%, amr).

**At a glance:** Benign · review: Single submitter · rsID rs531691068 · 1 submitter · ultra-rare (popmax 0.075%, amr)

## For patients & families {#patients}

This is a change in the HMBS gene that is classified as 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 | [HMBS](https://sugi.bio/atlas/gene/HMBS/) |
| Protein change (HGVS p.) | p.Arg22= |
| Coding change (HGVS c.) | c.66C>T |
| MANE Select transcript | [NM_000190](https://www.ncbi.nlm.nih.gov/nuccore/NM_000190) |
| dbSNP | [rs531691068](https://www.ncbi.nlm.nih.gov/snp/rs531691068/) |
| Variant type | single nucleotide variant |
| Location | chr11:119088287-119088287 (GRCh38) |
| ClinVar | [VCV1528776](https://www.ncbi.nlm.nih.gov/clinvar/variation/1528776/) |

**All HGVS expressions:** `LRG_1076:g.8411C>T`, `LRG_1076t1:c.66C>T`, `LRG_1076t2:c.15C>T`, `NC_000011.10:g.119088287C>T`, `NC_000011.9:g.118958997C>T`, `NG_008093.1:g.8411C>T`, `NM_000190.4:c.66C>T`, `NM_001024382.2:c.15C>T`, `NM_001258208.2:c.66C>T`, `NM_001258209.2:c.15C>T`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -5.146, GERP -4.65 — fast-evolving / accelerated position
- CADD: **PHRED 3.993**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.66 donor loss), 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 **0.075%** (amr) · FAF95 0.0575% · FAF99 0.0513% · 45/60,016 in the highest group · 73/1,614,052 alleles overall — ultra-rare (popmax 0.075%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.075% | 1,334 |
| Finnish (not grpmax-eligible) | 0.00312% | 32,005 |
| East Asian | 0.00223% | 44,890 |
| European (non-Finnish) | 0.00203% | 49,166 |
| African / African-American | 0.00133% | 75,018 |

*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}

**HMBS** population constraint: LOEUF 0.546, pLI 0.81406, missense-Z 1.3249; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *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):

- **acute intermittent porphyria** — Definitive (SD)

## Protein context {#protein}

Residue **22** lies in a UniProt-annotated variant site (in aip); a β-strand.

AlphaFold model confidence (whole protein): pLDDT 90.54, 79% of residues very-high.

**11 experimental structure(s)** (PDB): [3ECR](https://www.rcsb.org/structure/3ECR), [3EQ1](https://www.rcsb.org/structure/3EQ1), [5M6R](https://www.rcsb.org/structure/5M6R), [5M7F](https://www.rcsb.org/structure/5M7F), [7AAJ](https://www.rcsb.org/structure/7AAJ), [7AAK](https://www.rcsb.org/structure/7AAK) — incl. mutant structure 7AAK.

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

*Describes the biological roles of HMBS (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:** HMBS's established molecular role includes hydroxymethylbilane synthase activity.


### Pathways affected {#pathways}

HMBS participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Heme biosynthesis](https://reactome.org/content/detail/R-HSA-189451) | curated |

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

**Molecular function:** hydroxymethylbilane synthase activity.

**Biological process:** obsolete protoporphyrinogen IX biosynthetic process, heme biosynthetic process, heme B biosynthetic process.

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-23.

**Submitter consensus:** unanimous (1/1 Benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2025-04-23 |

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

## Similar variants {#similar}

Related HMBS variant pages (same residue, condition, or type): [HMBS p.Arg22His](/variant/hmbs-p-arg22his), [HMBS p.Arg22Cys](/variant/hmbs-p-arg22cys), [HMBS c.160+5G>C](/variant/hmbs-c-160-plus-5g-c), [HMBS c.345-1G>A](/variant/hmbs-c-345-minus-1g-a), [HMBS c.613-1G>A](/variant/hmbs-c-613-minus-1g-a), [HMBS c.826-2A>T](/variant/hmbs-c-826-minus-2a-t), [HMBS c.912+2T>C](/variant/hmbs-c-912-plus-2t-c), [HMBS c.913-1G>A](/variant/hmbs-c-913-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1528776). 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.*