Is FBP1 p.Pro222Ser (c.664C>T) pathogenic?

FBP1 p.Pro222Ser (c.664C>T) is classified Uncertain significance in FBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-27). AlphaMissense: likely benign (0.1027); Ultra-rare (popmax 0.0267%, amr); Associated with fructose-1,6-bisphosphatase deficiency.

What condition is associated with FBP1 p.Pro222Ser (c.664C>T)?

FBP1 p.Pro222Ser (c.664C>T) is associated with fructose-1,6-bisphosphatase deficiency (ClinVar).

How common is FBP1 p.Pro222Ser (c.664C>T) in the general population?

FBP1 p.Pro222Ser (c.664C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

How is Fructose-1,6-bisphosphatase deficiency inherited?

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

What do computational predictors say about FBP1 p.Pro222Ser (c.664C>T)?

AlphaMissense predicts likely benign (score 0.1027) — an in-silico prediction, not a clinical call.

FBP1 p.Pro222Ser

c.664C>T · rs1373961798 · VCV1509156

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1027 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fructose-1,6-bisphosphatase deficiency

Computational evidence

Protein change
AlphaMissense	0.1027	likely benign
REVEL	0.185	benign-leaning
SaProt	LLR -9.65	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 5.7	GERP -0.22, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 36 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	20.6	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 0.0267% Admixed American · 16/60,002 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.000991% 16/1,613,850 alleles · ultra-rare

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: FBP1
Protein: p.Pro222Ser
Coding: c.664C>T
MANE Select: NM_000507
dbSNP: rs1373961798
Type: single nucleotide variant
Location: chr9:94606856 (GRCh38)
Gene constraint: LOEUF 1.156 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.46 · 51 PDB
Residue 222: an α-helix

Full FBP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

fructose-1,6-bisphosphatase deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Fructose-1,6-bisphosphatase deficiency (Orphanet):

Inheritance: Autosomal recessive
Onset: All ages
Prevalence: 1-9 / 1 000 000 (Italy)

Similar variants

FBP1 c.426+1G>A Pathogenic ★★ same condition
FBP1 c.427-2A>G Likely pathogenic ★★ same condition
FBP1 p.Arg158Trp Pathogenic ★★ same condition
FBP1 p.Asp119Asn Pathogenic/Likely pathogenic ★★ same condition
FBP1 p.Glu281Lys Pathogenic/Likely pathogenic ★★ same condition
FBP1 p.Glu281Ter Pathogenic ★★ same condition
FBP1 p.Gly164Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
FBP1 p.Gly260Arg Pathogenic/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/fbp1-p-pro222ser (accessed [today's date]).

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