Is MAN1B1 p.Pro650= (c.1950C>T) pathogenic?

MAN1B1 p.Pro650= (c.1950C>T) is classified Conflicting classifications of pathogenicity in MAN1B1 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-01). Ultra-rare (popmax 0.0493%, mid); Associated with Rafiq syndrome.

What condition is associated with MAN1B1 p.Pro650= (c.1950C>T)?

MAN1B1 p.Pro650= (c.1950C>T) is associated with Rafiq syndrome (ClinVar).

How common is MAN1B1 p.Pro650= (c.1950C>T) in the general population?

MAN1B1 p.Pro650= (c.1950C>T) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

MAN1B1 p.Pro650=

c.1950C>T · rs377461918 · VCV435810

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0493%, mid)

Conditions

Rafiq syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.4	GERP -3.7
Overall
CADD	1.774	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0102%

Overall 0.0118% 190/1,613,828 alleles · ultra-rare exomes 171/1,461,620 · genomes 19/152,208 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
Remaining individualsnot grpmax-eligible	0.0272%	3,675
Admixed American	0.0217%	4,616
European (non-Finnish)	0.0125%	7,973
South Asian	0.00549%	18,218
African / African-American	0.00534%	18,729

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: MAN1B1
Protein: p.Pro650=
Coding: c.1950C>T
MANE Select: NM_016219
dbSNP: rs377461918
Type: single nucleotide variant
Location: chr9:137108441 (GRCh38)
Gene constraint: LOEUF 1.134 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.36 · 6 PDB

Full MAN1B1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Rafiq syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MAN1B1 p.Arg334Cys Pathogenic/Likely pathogenic ★★ same condition
MAN1B1 p.Gln162Ter Pathogenic ★★ same condition
MAN1B1 p.Gly359Ter Pathogenic/Likely pathogenic ★★ same condition
MAN1B1 c.*404T>C Uncertain significance ★★ same condition
MAN1B1 p.Ala112Val Uncertain significance ★★ ⚠ same condition
MAN1B1 p.Ala211Thr Uncertain significance ★★ ⚠ same condition
MAN1B1 p.Ala226Val Uncertain significance ★★ ⚠ same condition
MAN1B1 p.Ala294Val 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/man1b1-p-pro650 (accessed [today's date]).

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