Is LPP p.Asp358Glu (c.1074T>A) pathogenic?

LPP p.Asp358Glu (c.1074T>A) is classified Uncertain significance in LPP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-26). AlphaMissense: likely benign (0.1713); Very rare (popmax 0.000932%, nfe).

How common is LPP p.Asp358Glu (c.1074T>A) in the general population?

LPP p.Asp358Glu (c.1074T>A) is very rare (popmax 0.000932%, nfe) (gnomAD).

What do computational predictors say about LPP p.Asp358Glu (c.1074T>A)?

AlphaMissense predicts likely benign (score 0.1713) — an in-silico prediction, not a clinical call.

LPP p.Asp358Glu

c.1074T>A · rs777646093 · VCV2614561

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1713 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000932%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1713	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -4.81	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.073	GERP -0.71, phastCons 0.97
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	15.84	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 0.000932% European (non-Finnish) · 11/1,179,826 alleles

Filtering AF 0.0005% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000366%

Overall 0.000682% 11/1,613,366 alleles · very rare exomes 10/1,461,274 · genomes 1/152,092 · 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.Asp358Glu
Coding: c.1074T>A
MANE Select: NM_001375462
dbSNP: rs777646093
Type: single nucleotide variant
Location: chr3:188609805 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 358: the 'disordered' region

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-asp358glu (accessed [today's date]).

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