Is LPP p.Cys262Arg (c.784T>C) pathogenic?

LPP p.Cys262Arg (c.784T>C) is classified Uncertain significance in LPP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-11). AlphaMissense: likely benign (0.1455); Ultra-rare (popmax 0.0567%, amr).

How common is LPP p.Cys262Arg (c.784T>C) in the general population?

LPP p.Cys262Arg (c.784T>C) is ultra-rare (popmax 0.0567%, amr) (gnomAD).

What do computational predictors say about LPP p.Cys262Arg (c.784T>C)?

AlphaMissense predicts likely benign (score 0.1455) — an in-silico prediction, not a clinical call.

LPP p.Cys262Arg

c.784T>C · rs145531948 · VCV2395158

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1455 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1455	likely benign
REVEL	0.105	moderately benign-leaning
SaProt	LLR -4.04	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.56	GERP -4.8, phastCons 0.62
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	12.84	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 0.0567% Admixed American · 34/59,998 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0365%

Overall 0.0144% 233/1,614,064 alleles · ultra-rare exomes 216/1,461,880 · genomes 17/152,184 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0567%	1,765
Middle Eastern	0.0165%	6,058
European (non-Finnish)	0.0164%	6,114
Remaining individualsnot grpmax-eligible	0.0048%	20,836
East Asian	0.00223%	44,858
African / African-American	0.00133%	74,998

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.Cys262Arg
Coding: c.784T>C
MANE Select: NM_001375462
dbSNP: rs145531948
Type: single nucleotide variant
Location: chr3:188609515 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99

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-cys262arg (accessed [today's date]).

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