Is B2M p.Arg101Cys (c.301C>T) pathogenic?

B2M p.Arg101Cys (c.301C>T) is classified Uncertain significance in B2M (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-18). AlphaMissense: ambiguous (0.4383); Ultra-rare (popmax 0.0165%, mid); Associated with hypoproteinemia, hypercatabolic.

What condition is associated with B2M p.Arg101Cys (c.301C>T)?

B2M p.Arg101Cys (c.301C>T) is associated with hypoproteinemia, hypercatabolic (ClinVar).

How common is B2M p.Arg101Cys (c.301C>T) in the general population?

B2M p.Arg101Cys (c.301C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about B2M p.Arg101Cys (c.301C>T)?

AlphaMissense predicts ambiguous (score 0.4383) — an in-silico prediction, not a clinical call.

B2M p.Arg101Cys

c.301C>T · rs754841675 · VCV2177853

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4383 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hypoproteinemia, hypercatabolic

Computational evidence

Protein change
AlphaMissense	0.4383	ambiguous
REVEL	0.082	moderately benign-leaning
SaProt	LLR -13.15	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.26	GERP -2.9
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00123% 18/1,461,878 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)	0.00136%	73,752

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: B2M
Protein: p.Arg101Cys
Coding: c.301C>T
MANE Select: NM_004048
dbSNP: rs754841675
Type: single nucleotide variant
Location: chr15:44715656 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 94.43 · 1396 PDB
Residue 101: the ig-like c1-type domain; a β-strand

Full B2M gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypoproteinemia, hypercatabolic — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

B2M p.Arg101His Uncertain significance ★ ⚠ same residue
B2M p.Asp54Asn Uncertain significance ★★ ⚠ same condition
B2M p.Ile55Thr Uncertain significance ★★ ⚠ same condition
B2M p.Lys114Gln Uncertain significance ★★ ⚠ same condition
B2M p.Lys68Glu Uncertain significance ★★ ⚠ same condition
B2M p.Pro92Leu Uncertain significance ★★ ⚠ same condition
B2M c.67+12C>T Likely benign ★★ same condition
B2M c.67+19C>T Benign/Likely benign ★★ 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/b2m-p-arg101cys (accessed [today's date]).

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