Is MANBA p.Arg613Cys (c.1837C>T) pathogenic?

MANBA p.Arg613Cys (c.1837C>T) is classified Uncertain significance in MANBA (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-10). AlphaMissense: likely benign (0.1255); Ultra-rare (popmax 0.0165%, mid); Associated with beta-mannosidosis.

What condition is associated with MANBA p.Arg613Cys (c.1837C>T)?

MANBA p.Arg613Cys (c.1837C>T) is associated with beta-mannosidosis (ClinVar).

How common is MANBA p.Arg613Cys (c.1837C>T) in the general population?

MANBA p.Arg613Cys (c.1837C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

How is Beta-mannosidosis inherited?

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

What do computational predictors say about MANBA p.Arg613Cys (c.1837C>T)?

AlphaMissense predicts likely benign (score 0.1255) — an in-silico prediction, not a clinical call.

MANBA p.Arg613Cys

c.1837C>T · rs749814120 · VCV933478

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1255 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

beta-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.1255	likely benign
REVEL	0.169	moderately benign-leaning
SaProt	LLR -9.96	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 1.6, phastCons 0.86
Regional constraint	o/e 0.97	unconstrained · MANE · 129 kb · p 0.31 · regional, not allelic
Overall
CADD	23.9	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00463%

Overall 0.00577% 93/1,613,170 alleles · ultra-rare exomes 86/1,461,010 · genomes 7/152,160 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
Remaining individualsnot grpmax-eligible	0.0128%	7,806
South Asian	0.00659%	15,179
European (non-Finnish)	0.00619%	16,155
Admixed American	0.00333%	29,985
African / African-American	0.00267%	37,438
East Asian	0.00223%	44,876

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: MANBA
Protein: p.Arg613Cys
Coding: c.1837C>T
MANE Select: NM_005908
dbSNP: rs749814120
Type: single nucleotide variant
Location: chr4:102650569 (GRCh38)
Gene constraint: LOEUF 0.826 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.05
Residue 613: a UniProt-annotated variant site (in mansb; complete loss of enzyme activity)

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

Disease context

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

For Beta-mannosidosis (Orphanet):

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

Similar variants

MANBA p.Arg613His Uncertain significance ★★ ⚠ same residue
MANBA p.Arg613Leu Uncertain significance ★★ ⚠ same residue
MANBA p.Arg613= Likely benign ★ same residue
MANBA p.Arg613fs Pathogenic ★ same residue
MANBA c.1112+1G>T Likely pathogenic ★★ same condition
MANBA c.1231-1G>A Likely pathogenic ★★ same condition
MANBA c.1704+1G>T Likely pathogenic ★★ same condition
MANBA c.2158-2A>G 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/manba-p-arg613cys (accessed [today's date]).

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