Is FBP1 p.Pro235Arg (c.704C>G) pathogenic?

FBP1 p.Pro235Arg (c.704C>G) is classified Uncertain significance in FBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-04). AlphaMissense: likely benign (0.1072); Very rare (popmax 0.0017%, nfe); Associated with fructose-1,6-bisphosphatase deficiency.

What condition is associated with FBP1 p.Pro235Arg (c.704C>G)?

FBP1 p.Pro235Arg (c.704C>G) is associated with fructose-1,6-bisphosphatase deficiency (ClinVar).

How common is FBP1 p.Pro235Arg (c.704C>G) in the general population?

FBP1 p.Pro235Arg (c.704C>G) is very rare (popmax 0.0017%, nfe) (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.Pro235Arg (c.704C>G)?

AlphaMissense predicts likely benign (score 0.1072) — an in-silico prediction, not a clinical call.

FBP1 p.Pro235Arg

c.704C>G · VCV4753658

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1072 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

fructose-1,6-bisphosphatase deficiency

Computational evidence

Protein change
AlphaMissense	0.1072	likely benign
REVEL	0.072	moderately benign-leaning
SaProt	LLR -10.47	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.69	GERP -1.8, phastCons 0.002
Regional constraint	o/e 0.77	unconstrained · MANE · 36 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	17.15	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 0.0017% European (non-Finnish) · 20/1,179,176 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00143% 23/1,612,930 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,584
European (non-Finnish)grpmax	0.0017%	58,959
Remaining individualsnot grpmax-eligible	0.0016%	62,424
South Asian	0.0011%	91,010

Ashkenazi Jewish 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: FBP1
Protein: p.Pro235Arg
Coding: c.704C>G
MANE Select: NM_000507
Type: single nucleotide variant
Location: chr9:94606816 (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 235: a β-strand

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 p.Pro235Leu Uncertain significance ★★ ⚠ same residue
FBP1 p.Pro235= Conflicting classifications of pathogenicity ★ same residue
FBP1 p.Pro235fs Pathogenic/Likely pathogenic ★★ same residue
FBP1 p.Pro235Gln Uncertain significance ★ ⚠ same residue
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

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-pro235arg (accessed [today's date]).

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