Is LPP p.Arg140Trp (c.418C>T) pathogenic?

LPP p.Arg140Trp (c.418C>T) is classified Uncertain significance in LPP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-01-04). AlphaMissense: ambiguous (0.3405); Ultra-rare (popmax 0.0133%, amr); Associated with acute myeloid leukemia.

What condition is associated with LPP p.Arg140Trp (c.418C>T)?

LPP p.Arg140Trp (c.418C>T) is associated with acute myeloid leukemia (ClinVar).

How common is LPP p.Arg140Trp (c.418C>T) in the general population?

LPP p.Arg140Trp (c.418C>T) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about LPP p.Arg140Trp (c.418C>T)?

AlphaMissense predicts ambiguous (score 0.3405) — an in-silico prediction, not a clinical call.

LPP p.Arg140Trp

c.418C>T · rs201958080 · VCV2348186

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3405 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

acute myeloid leukemia

Computational evidence

Protein change
AlphaMissense	0.3405	ambiguous
REVEL	0.272	benign-leaning
SaProt	LLR -10.51	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.5, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	31.0	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 0.0133% Admixed American · 8/59,978 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.00192% 31/1,613,832 alleles · ultra-rare exomes 29/1,461,628 · genomes 2/152,204 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,497
European (non-Finnish)	0.00195%	51,299

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: LPP
Protein: p.Arg140Trp
Coding: c.418C>T
MANE Select: NM_001375462
dbSNP: rs201958080
Type: single nucleotide variant
Location: chr3:188524776 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 140: the 'disordered' region

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

Disease context

acute myeloid leukemia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LPP p.Arg140Gln Uncertain significance ★ ⚠ same residue
LPP p.Arg452Ter Conflicting classifications of pathogenicity ★ same condition
LPP p.Ser151Pro Uncertain significance ★ ⚠ same condition
LPP c.1113+51T>C Benign ★★ same type
LPP c.1240+249G>A Benign ★★ same type
LPP c.1240+75A>G Benign ★★ same type
LPP c.1410+155C>T Benign ★★ same type
LPP c.1410+157T>C Benign ★★ 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/lpp-p-arg140trp (accessed [today's date]).

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