Is MAN2B1 p.Pro593Ser (c.1777C>T) pathogenic?

MAN2B1 p.Pro593Ser (c.1777C>T) is classified Uncertain significance in MAN2B1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-01). AlphaMissense: likely benign (0.067); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with MAN2B1 p.Pro593Ser (c.1777C>T)?

MAN2B1 p.Pro593Ser (c.1777C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MAN2B1 p.Pro593Ser (c.1777C>T) in the general population?

MAN2B1 p.Pro593Ser (c.1777C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about MAN2B1 p.Pro593Ser (c.1777C>T)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

MAN2B1 p.Pro593Ser

c.1777C>T · VCV3542445

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -6.81	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 -2.3
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.03 · regional, not allelic
Overall
CADD	0.68	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 0.00134% African / African-American · 1/74,862 alleles

Filtering AF 0.00036% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000621% 10/1,609,458 alleles · very rare exomes 9/1,457,278 · genomes 1/152,180 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,862
European (non-Finnish)	0.000765%	130,730

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: MAN2B1
Protein: p.Pro593Ser
Coding: c.1777C>T
MANE Select: NM_000528
Type: single nucleotide variant
Location: chr19:12655747 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.78
Residue 593: a UniProt-annotated variant site (in mansa); a UniProt-annotated variant site (in mansa; uncertain significance)

Full MAN2B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAN2B1 p.Pro593= Likely benign ★★ same residue
MAN2B1 p.Pro197Arg Likely pathogenic ★★ same condition
MAN2B1 p.Ala559Glu Uncertain significance ★★ ⚠ same condition
MAN2B1 p.Ala559Val Uncertain significance ★★ ⚠ same condition
MAN2B1 p.Arg308Cys Uncertain significance ★★ ⚠ same condition
MAN2B1 p.Arg308His Uncertain significance ★★ ⚠ same condition
MAN2B1 p.Arg585Cys Uncertain significance ★★ ⚠ same condition
MAN2B1 p.Arg742His Uncertain significance ★★ ⚠ 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/man2b1-p-pro593ser (accessed [today's date]).

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