Is MAN2B2 p.Arg975Ser (c.2923C>A) pathogenic?

MAN2B2 p.Arg975Ser (c.2923C>A) is classified Uncertain significance in MAN2B2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-21). AlphaMissense: likely benign (0.1095); Rare (popmax 0.185%, nfe); Associated with congenital disorder of glycosylation type 1EE with or without immunodeficiency.

What condition is associated with MAN2B2 p.Arg975Ser (c.2923C>A)?

MAN2B2 p.Arg975Ser (c.2923C>A) is associated with congenital disorder of glycosylation type 1EE with or without immunodeficiency (ClinVar).

How common is MAN2B2 p.Arg975Ser (c.2923C>A) in the general population?

MAN2B2 p.Arg975Ser (c.2923C>A) is rare (popmax 0.185%, nfe) (gnomAD).

How is MAN2B2-CDG inherited?

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

What do computational predictors say about MAN2B2 p.Arg975Ser (c.2923C>A)?

AlphaMissense predicts likely benign (score 0.1095) — an in-silico prediction, not a clinical call.

MAN2B2 p.Arg975Ser

c.2923C>A · rs148481113 · VCV2347975

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1095 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.185%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital disorder of glycosylation type 1EE with or without immunodeficiency

Computational evidence

Protein change
AlphaMissense	0.1095	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -5.12	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 -1.3	GERP -0.24
Regional constraint	o/e 0.96	unconstrained · MANE · 46 kb · p 0.14 · regional, not allelic
Overall
CADD	5.69	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 0.185% European (non-Finnish) · 2,181/1,179,114 alleles

Filtering AF 0.178% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.176%

Overall 0.142% 2,281/1,611,622 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.185%	541
Remaining individualsnot grpmax-eligible	0.101%	989
Admixed American	0.0301%	3,318
African / African-American	0.0174%	5,761
Finnishnot grpmax-eligible	0.00628%	15,912
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,520
South Asian	0.0011%	90,812

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.Arg975Ser
Coding: c.2923C>A
MANE Select: NM_015274
dbSNP: rs148481113
Type: single nucleotide variant
Location: chr4:6620035 (GRCh38)
Gene constraint: LOEUF 1.023 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.55
Residue 975: the 'disordered' region

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

Disease context

congenital disorder of glycosylation type 1EE with or without immunodeficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For MAN2B2-CDG (Orphanet):

Inheritance: Autosomal recessive

Similar variants

MAN2B2 p.Arg975His Likely benign ★ same residue
MAN2B2 p.Trp284Ter Pathogenic/Likely pathogenic ★★ same condition
MAN2B2 p.Ala155Thr Uncertain significance ★★ ⚠ same condition
MAN2B2 p.Trp358Ter Likely pathogenic ★ same condition
MAN2B2 p.Gln408Ter Uncertain significance ★ same condition
MAN2B2 p.Glu790Lys Pathogenic same condition
MAN2B2 p.Gln615Ter Pathogenic/Likely pathogenic ★★ same type
MAN2B2 p.Ala868Thr 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-arg975ser (accessed [today's date]).

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