Is MAN2B1 p.Ile596= (c.1788C>A) pathogenic?

MAN2B1 p.Ile596= (c.1788C>A) is classified Likely benign in MAN2B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-09-01). Very rare (popmax 0.0011%, sas); Associated with alpha-mannosidosis.

What condition is associated with MAN2B1 p.Ile596= (c.1788C>A)?

MAN2B1 p.Ile596= (c.1788C>A) is associated with alpha-mannosidosis (ClinVar).

How common is MAN2B1 p.Ile596= (c.1788C>A) in the general population?

MAN2B1 p.Ile596= (c.1788C>A) is very rare (popmax 0.0011%, sas) (gnomAD).

How is Alpha-mannosidosis inherited?

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

MAN2B1 p.Ile596=

c.1788C>A · rs969379236 · VCV1552474

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

alpha-mannosidosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.011	strongly benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -1.3	GERP -2.6
Overall
CADD	0.122	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,842 alleles

Overall 0.000124% 2/1,609,118 alleles · very rare exomes 2/1,456,854 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,842
European (non-Finnish)	8.5e-05%	1,176,401

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.Ile596=
Coding: c.1788C>A
MANE Select: NM_000528
dbSNP: rs969379236
Type: single nucleotide variant
Location: chr19:12655736 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.78
Residue 596: 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.Ile596Ser Uncertain significance ★★ ⚠ same residue
MAN2B1 p.Ile596Asn 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-ile596 (accessed [today's date]).

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