Is MAN2B2 p.Ser441Pro (c.1321T>C) pathogenic?

MAN2B2 p.Ser441Pro (c.1321T>C) is classified Uncertain significance in MAN2B2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-27). AlphaMissense: ambiguous (0.3944); Very rare (popmax 0.000254%, nfe).

How common is MAN2B2 p.Ser441Pro (c.1321T>C) in the general population?

MAN2B2 p.Ser441Pro (c.1321T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about MAN2B2 p.Ser441Pro (c.1321T>C)?

AlphaMissense predicts ambiguous (score 0.3944) — an in-silico prediction, not a clinical call.

MAN2B2 p.Ser441Pro

c.1321T>C · VCV4102819

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3944 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3944	ambiguous
REVEL	0.252	benign-leaning
SaProt	LLR -11.84	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.91	GERP -2.3
Regional constraint	o/e 0.96	unconstrained · MANE · 46 kb · p 0.14 · regional, not allelic
Overall
CADD	1.162	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 0.000254% European (non-Finnish) · 3/1,180,032 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,700 alleles · very rare exomes 3/1,461,362 · genomes 0/152,338 · joint denominator

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.Ser441Pro
Coding: c.1321T>C
MANE Select: NM_015274
Type: single nucleotide variant
Location: chr4:6598270 (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.Ser441= Likely benign ★ 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-ser441pro (accessed [today's date]).

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