Is LPP p.Ser178Cys (c.533C>G) pathogenic?

LPP p.Ser178Cys (c.533C>G) is classified Uncertain significance in LPP (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-29). AlphaMissense: ambiguous (0.4241); Very rare (popmax 0.00223%, eas).

How common is LPP p.Ser178Cys (c.533C>G) in the general population?

LPP p.Ser178Cys (c.533C>G) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about LPP p.Ser178Cys (c.533C>G)?

AlphaMissense predicts ambiguous (score 0.4241) — an in-silico prediction, not a clinical call.

LPP p.Ser178Cys

c.533C>G · rs1236336023 · VCV2531111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4241 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4241	ambiguous
REVEL	0.235	benign-leaning
SaProt	LLR -8.81	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	29.0	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 0.00223% East Asian · 1/44,862 alleles

Overall 6.2e-05% 1/1,614,098 alleles · very rare exomes 1/1,461,884 · genomes 0/152,214 · 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.Ser178Cys
Coding: c.533C>G
MANE Select: NM_001375462
dbSNP: rs1236336023
Type: single nucleotide variant
Location: chr3:188609264 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 178: 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-ser178cys (accessed [today's date]).

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