Is MPIG6B p.Arg83His (c.248G>A) pathogenic?

MPIG6B p.Arg83His (c.248G>A) is classified Uncertain significance in MPIG6B (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.602); Very rare (popmax 0.000932%, nfe); Associated with thrombocytopenia, anemia, and myelofibrosis.

What condition is associated with MPIG6B p.Arg83His (c.248G>A)?

MPIG6B p.Arg83His (c.248G>A) is associated with thrombocytopenia, anemia, and myelofibrosis (ClinVar).

How common is MPIG6B p.Arg83His (c.248G>A) in the general population?

MPIG6B p.Arg83His (c.248G>A) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about MPIG6B p.Arg83His (c.248G>A)?

AlphaMissense predicts likely pathogenic (score 0.602) — an in-silico prediction, not a clinical call.

MPIG6B p.Arg83His

c.248G>A · rs200855070 · VCV828136

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.602 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

thrombocytopenia, anemia, and myelofibrosis

Computational evidence

Protein change
AlphaMissense	0.602	likely pathogenic
REVEL	0.342	indeterminate
SaProt	LLR -10.37	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Overall
CADD	28.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000932% European (non-Finnish) · 11/1,179,664 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.00384% 62/1,613,092 alleles · very rare exomes 57/1,460,892 · genomes 5/152,200 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.152%	656
Remaining individualsnot grpmax-eligible	0.00961%	10,409
European (non-Finnish)grpmax	0.000932%	107,242

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MPIG6B
Protein: p.Arg83His
Coding: c.248G>A
MANE Select: NM_138272
dbSNP: rs200855070
Type: single nucleotide variant
Location: chr6:31723825 (GRCh38)
Gene constraint: LOEUF 1.276 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.01 · 1 PDB

Full MPIG6B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

thrombocytopenia, anemia, and myelofibrosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MPIG6B p.Arg175Ter Pathogenic/Likely pathogenic ★★ same condition
MPIG6B p.Cys108Ter Pathogenic ★★ same condition
MPIG6B p.Thr186= Likely pathogenic ★★ same condition
MPIG6B p.Ala52Thr Uncertain significance ★★ ⚠ same condition
MPIG6B p.Trp163Ter Pathogenic ★ same condition
MPIG6B p.Cys108Phe Uncertain significance ★ ⚠ same condition
MPIG6B p.Pro173Gln Conflicting classifications of pathogenicity ★ ⚠ same condition
MPIG6B p.Pro191= Uncertain significance ★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mpig6b-p-arg83his (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown