Is B2M p.Ser53= (c.159C>T) pathogenic?

B2M p.Ser53= (c.159C>T) is classified Likely benign in B2M (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-24). Ultra-rare (popmax 0.0267%, amr); Associated with hypoproteinemia, hypercatabolic.

What condition is associated with B2M p.Ser53= (c.159C>T)?

B2M p.Ser53= (c.159C>T) is associated with hypoproteinemia, hypercatabolic (ClinVar).

How common is B2M p.Ser53= (c.159C>T) in the general population?

B2M p.Ser53= (c.159C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

B2M p.Ser53=

c.159C>T · rs200164063 · VCV719660

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Conditions

hypoproteinemia, hypercatabolic

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP -8.7	GERP -3.7
Overall
CADD	2.295	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0267% Admixed American · 16/60,014 alleles

Filtering AF 0.0216% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0207%

Overall 0.0205% 331/1,614,040 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Admixed Americangrpmax	0.0267%	3,751
European (non-Finnish)	0.024%	4,170
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
Finnishnot grpmax-eligible	0.00781%	12,800
African / African-American	0.00533%	18,747
South Asian	0.00329%	30,359

Remaining individuals 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: B2M
Protein: p.Ser53=
Coding: c.159C>T
MANE Select: NM_004048
dbSNP: rs200164063
Type: single nucleotide variant
Location: chr15:44715514 (GRCh38)
Gene constraint: LOEUF 0.501 · pLI 0.97 (gnomAD)
Structure: AlphaFold pLDDT 94.43 · 1396 PDB
Residue 53: a disulfide bond; a β-strand; the ig-like c1-type domain

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.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-ser53 (accessed [today's date]).

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