Is FBP1 p.Ser321Phe (c.962C>T) pathogenic?

FBP1 p.Ser321Phe (c.962C>T) is classified Uncertain significance in FBP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-17). AlphaMissense: likely pathogenic (0.9855); Ultra-rare (popmax 0.0165%, mid).

How common is FBP1 p.Ser321Phe (c.962C>T) in the general population?

FBP1 p.Ser321Phe (c.962C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about FBP1 p.Ser321Phe (c.962C>T)?

AlphaMissense predicts likely pathogenic (score 0.9855) — an in-silico prediction, not a clinical call.

FBP1 p.Ser321Phe

c.962C>T · VCV3339475

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9855 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9855	likely pathogenic · top 10% in FBP1
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -14.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 36 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	27.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0165% Middle Eastern · 1/6,060 alleles

Filtering AF 0.00726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000682% 11/1,614,030 alleles · ultra-rare exomes 11/1,461,834 · genomes 0/152,196 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,060
East Asian	0.0156%	6,410
European (non-Finnish)	0.000254%	393,331

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.Ser321Phe
Coding: c.962C>T
MANE Select: NM_000507
Type: single nucleotide variant
Location: chr9:94603436 (GRCh38)
Gene constraint: LOEUF 1.156 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 94.46 · 51 PDB

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

Similar variants

FBP1 p.Ser321fs Pathogenic ★ same residue
FBP1 c.426+1G>A Pathogenic ★★ same type
FBP1 c.427-2A>G Likely pathogenic ★★ same type
FBP1 p.Arg158Trp Pathogenic ★★ same type
FBP1 p.Asp119Asn Pathogenic/Likely pathogenic ★★ same type
FBP1 p.Glu281Lys Pathogenic/Likely pathogenic ★★ same type
FBP1 p.Glu281Ter Pathogenic ★★ same type
FBP1 p.Gly164Ser Pathogenic/Likely pathogenic ★★ ⚠ same type

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-ser321phe (accessed [today's date]).

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