Is MAN2B1 p.Pro69Ala (c.205C>G) pathogenic?

MAN2B1 p.Pro69Ala (c.205C>G) is classified Likely benign in MAN2B1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0415); Very rare (popmax 0.00167%, amr); Associated with alpha-mannosidosis.

What condition is associated with MAN2B1 p.Pro69Ala (c.205C>G)?

MAN2B1 p.Pro69Ala (c.205C>G) is associated with alpha-mannosidosis (ClinVar).

How common is MAN2B1 p.Pro69Ala (c.205C>G) in the general population?

MAN2B1 p.Pro69Ala (c.205C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Alpha-mannosidosis inherited?

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

What do computational predictors say about MAN2B1 p.Pro69Ala (c.205C>G)?

AlphaMissense predicts likely benign (score 0.0415) — an in-silico prediction, not a clinical call.

MAN2B1 p.Pro69Ala

c.205C>G · rs200704731 · VCV2062040

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0415 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

alpha-mannosidosis

Computational evidence

Protein change
AlphaMissense	0.0415	likely benign
REVEL	0.334	indeterminate
SaProt	LLR -6.47	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.5	GERP -0.85, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 20 kb · p 0.03 · regional, not allelic
Overall
CADD	15.95	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 0.00167% Admixed American · 1/59,998 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.00558% 90/1,614,026 alleles · very rare exomes 82/1,461,838 · genomes 8/152,188 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.113%	889
Remaining individualsnot grpmax-eligible	0.0176%	5,681
Admixed Americangrpmax	0.00167%	59,998
European (non-Finnish)	0.000508%	196,672

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro69Ala
Coding: c.205C>G
MANE Select: NM_000528
dbSNP: rs200704731
Type: single nucleotide variant
Location: chr19:12665760 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.78

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

Disease context

alpha-mannosidosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Alpha-mannosidosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy, Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

MAN2B1 c.1026+2T>G Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1109+1G>C Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1527+1G>A Likely pathogenic ★★ same condition
MAN2B1 c.1527+1G>T Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1527+2T>G Pathogenic ★★ same condition
MAN2B1 c.1528-1G>A Pathogenic/Likely pathogenic ★★ same condition
MAN2B1 c.1528-1G>T Likely pathogenic ★★ same condition
MAN2B1 c.159+2T>C Likely pathogenic ★★ 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-pro69ala (accessed [today's date]).

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