Is LPP p.Pro153Thr (c.457C>A) pathogenic?

LPP p.Pro153Thr (c.457C>A) is classified Uncertain significance in LPP (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely benign (0.0537); Very rare (popmax 0.0022%, nfe).

How common is LPP p.Pro153Thr (c.457C>A) in the general population?

LPP p.Pro153Thr (c.457C>A) is very rare (popmax 0.0022%, nfe) (gnomAD).

What do computational predictors say about LPP p.Pro153Thr (c.457C>A)?

AlphaMissense predicts likely benign (score 0.0537) — an in-silico prediction, not a clinical call.

LPP p.Pro153Thr

c.457C>A · rs780877086 · VCV1050142

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0537 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0537	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.66	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 0.76	GERP -3, phastCons 0.98
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	20.9	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 0.0022% European (non-Finnish) · 26/1,179,358 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00161% 26/1,613,002 alleles · very rare exomes 26/1,460,918 · genomes 0/152,084 · 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.Pro153Thr
Coding: c.457C>A
MANE Select: NM_001375462
dbSNP: rs780877086
Type: single nucleotide variant
Location: chr3:188609188 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 153: 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-pro153thr (accessed [today's date]).

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