# NM_138272.3(MPIG6B):c.621G>T (p.Pro207=)

https://sugi.bio/variant/mpig6b-p-pro207

## Summary

**MPIG6B p.Pro207= (c.621G>T)** is classified **Uncertain significance** in MPIG6B (ClinVar, Single submitter, 2 submitters; last evaluated 2023-09-27). Ultra-rare (popmax 0.0186%, nfe); Associated with thrombocytopenia.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs147600887 · 2 submitters · 1 linked condition · ultra-rare (popmax 0.0186%, nfe)

## For patients & families {#patients}

This is a change in the MPIG6B gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to thrombocytopenia.

*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 | [MPIG6B](https://sugi.bio/atlas/gene/MPIG6B/) |
| Protein change (HGVS p.) | p.Pro207= |
| Coding change (HGVS c.) | c.621G>T |
| MANE Select transcript | [NM_138272](https://www.ncbi.nlm.nih.gov/nuccore/NM_138272) |
| dbSNP | [rs147600887](https://www.ncbi.nlm.nih.gov/snp/rs147600887/) |
| Variant type | single nucleotide variant |
| Location | chr6:31724844-31724844 (GRCh38) |
| ClinVar | [VCV988872](https://www.ncbi.nlm.nih.gov/clinvar/variation/988872/) |

**All HGVS expressions:** `LRG_1003:g.6501G>T`, `LRG_1003t1:c.640G>T`, `LRG_1003t2:c.621G>T`, `NC_000006.11:g.31692621G>T`, `NC_000006.12:g.31724844G>T`, `NG_029044.2:g.6501G>T`, `NM_025260.3:c.640G>T`, `NM_025260.4:c.640G>T`, `NM_138272.3:c.621G>T`, `NM_138273.3:c.549G>T`, `NM_138274.3:c.508G>T`, `NM_138275.3:c.489G>T`, `NM_138277.3:c.640G>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.30) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 8.222, GERP 1.44, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 18.49**. 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 **0.30**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.30**, acceptor gain **0.00**, donor gain **0.00**.
- Pangolin: Δ**0.43** (loss), gain 0.01 / loss 0.43. Agrees with SpliceAI. 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 (gnomAD v4.1): grpmax **0.0186%** (nfe) · FAF95 0.0166% · FAF99 0.0158% · 220/1,179,916 in the highest group · 259/1,613,774 alleles overall — ultra-rare (popmax 0.0186%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.0437% | 2,286 |
| European (non-Finnish) (grpmax) | 0.0186% | 5,363 |
| Remaining individuals (not grpmax-eligible) | 0.0096% | 10,413 |
| African / African-American | 0.00668% | 14,966 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**MPIG6B** population constraint: LOEUF 1.276, pLI 1.4673e-07, missense-Z 0.5734. *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):

- **thrombocytopenia, anemia, and myelofibrosis** — Definitive (AR)

## Protein context {#protein}

Residue **207** lies in a UniProt-annotated variant site (in thamy; increased protein degradation; decreased enhancement of hematopoietic lineage differentiation).

AlphaFold model confidence (whole protein): pLDDT 73.01, 38% of residues very-high.

**1 experimental structure(s)** (PDB): [6R0X](https://www.rcsb.org/structure/6R0X).

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

*Describes the biological roles of MPIG6B (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}

MPIG6B participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [GPVI-mediated activation cascade](https://reactome.org/content/detail/R-HSA-114604) | curated |

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

**Biological process:** negative regulation of signal transduction, erythrocyte differentiation, megakaryocyte differentiation.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2023-09-27.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2020–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Birmingham Platelet Group; University of Birmingham | Uncertain significance | no assertion criteria provided | research | 2020-05-01 |
| Mayo Clinic Laboratories, Mayo Clinic | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-27 |

## Associated conditions {#conditions}

[thrombocytopenia](https://sugi.bio/atlas/disease/thrombocytopenia/).

**Reported phenotype names (ClinVar):** Abnormal bleeding, Thrombocytopenia, not provided, none provided, Bleeding diathesis.

## Similar variants {#similar}

Related MPIG6B variant pages (same residue, condition, or type): [MPIG6B p.Trp44Cys](/variant/mpig6b-p-trp44cys), [MPIG6B p.Arg175Ter](/variant/mpig6b-p-arg175ter), [MPIG6B p.Cys108Ter](/variant/mpig6b-p-cys108ter), [MPIG6B p.Thr186=](/variant/mpig6b-p-thr186), [MPIG6B c.542-9C>G](/variant/mpig6b-c-542-minus-9c-g), [MPIG6B p.Ala21Gly](/variant/mpig6b-p-ala21gly), [MPIG6B p.Ala52Thr](/variant/mpig6b-p-ala52thr), [MPIG6B p.Arg83His](/variant/mpig6b-p-arg83his).

### 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 988872). 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.*