Is FDPS p.Leu14Arg (c.41T>G) pathogenic?

FDPS p.Leu14Arg (c.41T>G) is classified Uncertain significance in FDPS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-01). AlphaMissense: likely benign (0.2009); Ultra-rare (popmax 0.0182%, mid).

How common is FDPS p.Leu14Arg (c.41T>G) in the general population?

FDPS p.Leu14Arg (c.41T>G) is ultra-rare (popmax 0.0182%, mid) (gnomAD).

What do computational predictors say about FDPS p.Leu14Arg (c.41T>G)?

AlphaMissense predicts likely benign (score 0.2009) — an in-silico prediction, not a clinical call.

FDPS p.Leu14Arg

c.41T>G · VCV4668157

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2009 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0182%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2009	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -6.74	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 0.54, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 11 kb · p 1.1e-06 · regional, not allelic
Overall
CADD	24.6	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 0.0182% Middle Eastern · 1/5,500 alleles

Filtering AF 0.00349% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00316%

Overall 0.00361% 57/1,576,862 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0182%	5,500
Remaining individualsnot grpmax-eligible	0.00493%	20,292
European (non-Finnish)	0.00449%	22,262
African / African-American	0.00134%	74,390

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.Leu14Arg
Coding: c.41T>G
MANE Select: NM_002004
Type: single nucleotide variant
Location: chr1:155309830 (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

Similar variants

FDPS c.684+2T>G Likely pathogenic ★ same type
FDPS p.Ala119Val Uncertain significance ★ ⚠ same type
FDPS p.Arg110Gly Uncertain significance ★ ⚠ same type
FDPS p.Arg110Trp Uncertain significance ★ ⚠ same type
FDPS p.Arg214Gln Uncertain significance ★ ⚠ same type
FDPS p.Arg23Gln Uncertain significance ★ ⚠ same type
FDPS p.Arg23Trp Uncertain significance ★ ⚠ same type
FDPS p.Arg25Lys 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-leu14arg (accessed [today's date]).

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