Is MAN2B2 p.Arg330Cys (c.988C>T) pathogenic?

MAN2B2 p.Arg330Cys (c.988C>T) is classified Uncertain significance in MAN2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-28). AlphaMissense: likely benign (0.1241); Ultra-rare (popmax 0.0134%, eas).

How common is MAN2B2 p.Arg330Cys (c.988C>T) in the general population?

MAN2B2 p.Arg330Cys (c.988C>T) is ultra-rare (popmax 0.0134%, eas) (gnomAD).

What do computational predictors say about MAN2B2 p.Arg330Cys (c.988C>T)?

AlphaMissense predicts likely benign (score 0.1241) — an in-silico prediction, not a clinical call.

MAN2B2 p.Arg330Cys

c.988C>T · rs772632113 · VCV2491463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1241 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0134%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1241	likely benign
REVEL	0.388	indeterminate
SaProt	LLR -12.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -1.5
Regional constraint	o/e 0.96	unconstrained · MANE · 46 kb · p 0.14 · regional, not allelic
Overall
CADD	22.6	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

Grpmax group 0.0134% East Asian · 6/44,898 alleles

Filtering AF 0.00579% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00394%

Overall 0.00105% 17/1,613,356 alleles · ultra-rare exomes 14/1,461,116 · genomes 3/152,240 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0134%	7,483
Remaining individualsnot grpmax-eligible	0.0032%	31,230
South Asian	0.0022%	45,534
Finnishnot grpmax-eligible	0.00157%	63,544
European (non-Finnish)	0.000508%	196,670

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: MAN2B2
Protein: p.Arg330Cys
Coding: c.988C>T
MANE Select: NM_015274
dbSNP: rs772632113
Type: single nucleotide variant
Location: chr4:6594663 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.55

Full MAN2B2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MAN2B2 p.Arg330His Uncertain significance ★ ⚠ same residue
MAN2B2 p.Gln615Ter Pathogenic/Likely pathogenic ★★ same type
MAN2B2 p.Trp284Ter Pathogenic/Likely pathogenic ★★ same type
MAN2B2 p.Ala155Thr Uncertain significance ★★ ⚠ same type
MAN2B2 p.Ala868Thr Uncertain significance ★★ ⚠ same type
MAN2B2 p.Arg411His Uncertain significance ★★ ⚠ same type
MAN2B2 p.Arg447Gly Uncertain significance ★★ ⚠ same type
MAN2B2 p.Arg683Gln Uncertain significance ★★ ⚠ same type

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/man2b2-p-arg330cys (accessed [today's date]).

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