Is FDPS p.Trp26Ter (c.78G>A) pathogenic?

FDPS p.Trp26Ter (c.78G>A) is classified Uncertain significance in FDPS (ClinVar, Single submitter, 2 submitters; last evaluated 2025-03-05). Ultra-rare (popmax 0.012%, afr); Associated with response to aminobisphosphonates.

What condition is associated with FDPS p.Trp26Ter (c.78G>A)?

FDPS p.Trp26Ter (c.78G>A) is associated with response to aminobisphosphonates (ClinVar).

How common is FDPS p.Trp26Ter (c.78G>A) in the general population?

FDPS p.Trp26Ter (c.78G>A) is ultra-rare (popmax 0.012%, afr) (gnomAD).

FDPS p.Trp26Ter

c.78G>A · VCV4279714

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

response to aminobisphosphonates

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 11
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	GERP -3.1, phastCons 1
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,700 alleles

Filtering AF 0.00625% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00469%

Overall 0.000566% 9/1,589,546 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: FDPS
Protein: p.Trp26Ter
Coding: c.78G>A
MANE Select: NM_002004
Type: single nucleotide variant
Location: chr1:155309867 (GRCh38)
Gene constraint: LOEUF 0.744 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.27 · 92 PDB

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

Disease context

response to aminobisphosphonates

Similar variants

FDPS p.Arg48Cys Benign same condition
FDPS p.Ile120Thr Benign same condition
FDPS p.Ser63= Benign same condition
FDPS p.Tyr219= Likely benign same condition
FDPS p.Val364Ala Benign same condition
FDPS c.684+2T>G Likely pathogenic ★ same type
FDPS p.Ala119Val Uncertain significance ★ ⚠ same type
FDPS p.Arg110Gly Uncertain significance ★ ⚠ 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/fdps-p-trp26ter (accessed [today's date]).

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