Is B2M p.Arg23Cys (c.67C>T) pathogenic?

B2M p.Arg23Cys (c.67C>T) is classified Uncertain significance in B2M (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.5709); Absent from gnomAD v4.1; Associated with amyloidosis, hereditary systemic 6.

What condition is associated with B2M p.Arg23Cys (c.67C>T)?

B2M p.Arg23Cys (c.67C>T) is associated with amyloidosis, hereditary systemic 6, hypoproteinemia, hypercatabolic (ClinVar).

How common is B2M p.Arg23Cys (c.67C>T) in the general population?

B2M p.Arg23Cys (c.67C>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary ATTR amyloidosis inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about B2M p.Arg23Cys (c.67C>T)?

AlphaMissense predicts likely pathogenic (score 0.5709) — an in-silico prediction, not a clinical call.

B2M p.Arg23Cys

c.67C>T · VCV3577177

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5709 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

amyloidosis, hereditary systemic 6

Computational evidence

Protein change
AlphaMissense	0.5709	likely pathogenic
REVEL	0.083	moderately benign-leaning
SaProt	LLR -10.23	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	Δ0.21	donor gain · deltas
Constraint at this position
Conservation	phyloP 0.91	GERP 1.8, phastCons 0.35
Overall
CADD	26.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: B2M
Protein: p.Arg23Cys
Coding: c.67C>T
MANE Select: NM_004048
Type: single nucleotide variant
Location: chr15:44711613 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 94.43 · 1396 PDB
Residue 23: a β-strand

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

Disease context

amyloidosis, hereditary systemic 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hypoproteinemia, hypercatabolic

For Hereditary ATTR amyloidosis (Orphanet):

Inheritance: Autosomal dominant
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

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
B2M c.68-13C>T 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-arg23cys (accessed [today's date]).

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