Is MAN2B2 p.Pro8Ser (c.22C>T) pathogenic?

MAN2B2 p.Pro8Ser (c.22C>T) is classified Uncertain significance in MAN2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.0963); Ultra-rare (popmax 0.037%, nfe).

How common is MAN2B2 p.Pro8Ser (c.22C>T) in the general population?

MAN2B2 p.Pro8Ser (c.22C>T) is ultra-rare (popmax 0.037%, nfe) (gnomAD).

What do computational predictors say about MAN2B2 p.Pro8Ser (c.22C>T)?

AlphaMissense predicts likely benign (score 0.0963) — an in-silico prediction, not a clinical call.

MAN2B2 p.Pro8Ser

c.22C>T · rs374156683 · VCV2357772

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0963 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.037%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0963	likely benign
REVEL	0.19	benign-leaning
SaProt	LLR -6.62	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 0.73	GERP -1.4, phastCons 0.002
Regional constraint	o/e 0.96	unconstrained · MANE · 46 kb · p 0.14 · regional, not allelic
Overall
CADD	14.56	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 0.037% European (non-Finnish) · 423/1,142,832 alleles

Filtering AF 0.0341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0329%

Overall 0.0294% 451/1,532,870 alleles · ultra-rare exomes 420/1,380,636 · genomes 31/152,234 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.037%	2,702
Remaining individualsnot grpmax-eligible	0.0235%	4,262
Finnishnot grpmax-eligible	0.0171%	5,857
African / African-American	0.00548%	18,232
Admixed American	0.00389%	25,674

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.Pro8Ser
Coding: c.22C>T
MANE Select: NM_015274
dbSNP: rs374156683
Type: single nucleotide variant
Location: chr4:6575232 (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.Pro8Leu 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-pro8ser (accessed [today's date]).

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