Is LPP p.Arg22Trp (c.64C>T) pathogenic?

LPP p.Arg22Trp (c.64C>T) is classified Likely benign in LPP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-09-26). AlphaMissense: likely pathogenic (0.9237); Ultra-rare (popmax 0.0267%, amr); Associated with LPP-related disorder.

What condition is associated with LPP p.Arg22Trp (c.64C>T)?

LPP p.Arg22Trp (c.64C>T) is associated with LPP-related disorder (ClinVar).

How common is LPP p.Arg22Trp (c.64C>T) in the general population?

LPP p.Arg22Trp (c.64C>T) is ultra-rare (popmax 0.0267%, amr) (gnomAD).

What do computational predictors say about LPP p.Arg22Trp (c.64C>T)?

AlphaMissense predicts likely pathogenic (score 0.9237) — an in-silico prediction, not a clinical call.

LPP p.Arg22Trp

c.64C>T · rs183529256 · VCV3034955

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9237 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

LPP-related disorder

Computational evidence

Protein change
AlphaMissense	0.9237	likely pathogenic
REVEL	0.256	benign-leaning
SaProt	LLR -7.92	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.8, phastCons 0.99
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	28.9	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 0.0267% Admixed American · 16/60,030 alleles

Filtering AF 0.0166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.0152% 246/1,614,148 alleles · ultra-rare exomes 230/1,461,836 · genomes 16/152,312 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0267%	3,752
European (non-Finnish)	0.0173%	5,784
Middle Eastern	0.0165%	6,062
African / African-American	0.012%	8,338
South Asian	0.00988%	10,120
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,803
Remaining individualsnot grpmax-eligible	0.0064%	15,627
East Asian	0.00223%	44,888

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.Arg22Trp
Coding: c.64C>T
MANE Select: NM_001375462
dbSNP: rs183529256
Type: single nucleotide variant
Location: chr3:188406184 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 22: the 'disordered' region

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

Disease context

LPP-related disorder

Similar variants

LPP c.1589+8A>G Likely benign same condition
LPP p.Ala302= Likely benign same condition
LPP p.Gly245= Likely benign same condition
LPP p.Pro363Ser Benign same condition
LPP p.Ser145= Likely benign same condition
LPP p.Thr212Met Likely benign ⚠ same condition
LPP p.Arg140Trp Uncertain significance ★★ ⚠ same type
LPP c.1113+51T>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-arg22trp (accessed [today's date]).

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