Is LPP p.Arg535= (c.1605A>G) pathogenic?

LPP p.Arg535= (c.1605A>G) is classified Benign in LPP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-11-12). Common (popmax 51.4%, nfe) — too common for a highly-penetrant pathogenic allele.

LPP p.Arg535=

Q: How common is LPP p.Arg535= (c.1605A>G) in the general population?

LPP p.Arg535= (c.1605A>G) is common (popmax 51.4%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1605A>G · rs1136644 · VCV1225309

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 51.4%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.76	GERP -2.1, phastCons 0.99
Overall
CADD	8.738	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 51.4% European (non-Finnish) · 606,549/1,179,612 alleles

Filtering AF 51.3% ClinGen BA1/BS1 input FAF95, joint · FAF99 51.3%

Overall 49.3% 795,903/1,613,368 alleles · common exomes 729,110/1,461,498 · genomes 66,793/151,870 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	57.6%	2
Amishnot grpmax-eligible	53.4%	2
European (non-Finnish)grpmax	51.4%	2
Middle Eastern	51.2%	2
Remaining individualsnot grpmax-eligible	47.6%	2
South Asian	45%	2
East Asian	44.1%	2
Ashkenazi Jewishnot grpmax-eligible	43.3%	2
Admixed American	42.1%	2
African / African-American	27.2%	4

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg535=
Coding: c.1605A>G
MANE Select: NM_001375462
dbSNP: rs1136644
Type: single nucleotide variant
Location: chr3:188872658 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 535: the lim zinc-binding 3 domain

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

Similar variants

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
LPP c.1410+165T>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-arg535 (accessed [today's date]).

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