Is LPP p.Pro467Arg (c.1400C>G) pathogenic?

LPP p.Pro467Arg (c.1400C>G) is classified Uncertain significance in LPP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-06). AlphaMissense: ambiguous (0.3566); Very rare (popmax 0.000254%, nfe).

How common is LPP p.Pro467Arg (c.1400C>G) in the general population?

LPP p.Pro467Arg (c.1400C>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about LPP p.Pro467Arg (c.1400C>G)?

AlphaMissense predicts ambiguous (score 0.3566) — an in-silico prediction, not a clinical call.

LPP p.Pro467Arg

c.1400C>G · rs757981493 · VCV2235144

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Computational evidence

Protein change
AlphaMissense	0.3566	ambiguous
REVEL	0.58	indeterminate
SaProt	LLR -7.67	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	25.4	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 0.000254% European (non-Finnish) · 3/1,179,974 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,613,960 alleles · very rare exomes 3/1,461,830 · genomes 0/152,130 · joint denominator

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.Pro467Arg
Coding: c.1400C>G
MANE Select: NM_001375462
dbSNP: rs757981493
Type: single nucleotide variant
Location: chr3:188760272 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 467: the lim zinc-binding 1 domain

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

Similar variants

LPP p.Pro467Leu Uncertain significance ★ ⚠ same residue
LPP p.Arg140Trp Uncertain significance ★★ ⚠ same type
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
LPP c.1410+162G>A 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-pro467arg (accessed [today's date]).

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