Is MAN2B1 p.Pro976Ser (c.2926C>T) pathogenic?

MAN2B1 p.Pro976Ser (c.2926C>T) is classified Uncertain significance in MAN2B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0805); Very rare (popmax 0.00167%, amr); Associated with alpha-mannosidosis.

What condition is associated with MAN2B1 p.Pro976Ser (c.2926C>T)?

MAN2B1 p.Pro976Ser (c.2926C>T) is associated with alpha-mannosidosis (ClinVar).

How common is MAN2B1 p.Pro976Ser (c.2926C>T) in the general population?

MAN2B1 p.Pro976Ser (c.2926C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Alpha-mannosidosis inherited?

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

What do computational predictors say about MAN2B1 p.Pro976Ser (c.2926C>T)?

AlphaMissense predicts likely benign (score 0.0805) — an in-silico prediction, not a clinical call.

MAN2B1 p.Pro976Ser

c.2926C>T · VCV4755311

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0805 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

alpha-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.0805	likely benign
REVEL	0.086	moderately benign-leaning
SaProt	LLR -7.18	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.03 · regional, not allelic
Overall
CADD	12.38	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00167% Admixed American · 1/59,976 alleles

Overall 0.000124% 2/1,607,948 alleles · very rare exomes 1/1,455,902 · genomes 1/152,046 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,976
Remaining individualsnot grpmax-eligible	0.0016%	62,310

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: MAN2B1
Protein: p.Pro976Ser
Coding: c.2926C>T
MANE Select: NM_000528
Type: single nucleotide variant
Location: chr19:12646730 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.78
Residue 976: a UniProt-annotated variant site (in mansa); a UniProt-annotated variant site (in mansa; uncertain significance)

Full MAN2B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

alpha-mannosidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alpha-mannosidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

MAN2B1 p.Pro976Arg Uncertain significance ★ ⚠ same residue
MAN2B1 p.Pro976Leu Uncertain significance ⚠ same residue
MAN2B1 c.1026+2T>G Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1109+1G>C Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1527+1G>A Likely pathogenic ★★ same condition
MAN2B1 c.1527+1G>T Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1527+2T>G Pathogenic ★★ same condition
MAN2B1 c.1528-1G>A Pathogenic/Likely pathogenic ★★ 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/man2b1-p-pro976ser (accessed [today's date]).

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