Is LPP p.Pro57Ala (c.169C>G) pathogenic?

LPP p.Pro57Ala (c.169C>G) is classified Uncertain significance in LPP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-27). AlphaMissense: likely pathogenic (0.6253); Very rare (popmax 0.00729%, nfe).

How common is LPP p.Pro57Ala (c.169C>G) in the general population?

LPP p.Pro57Ala (c.169C>G) is very rare (popmax 0.00729%, nfe) (gnomAD).

What do computational predictors say about LPP p.Pro57Ala (c.169C>G)?

AlphaMissense predicts likely pathogenic (score 0.6253) — an in-silico prediction, not a clinical call.

LPP p.Pro57Ala

c.169C>G · rs145658316 · VCV2263371

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6253 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00729%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.6253	likely pathogenic
REVEL	0.318	indeterminate
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.8, phastCons 1
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	26.4	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 0.00729% European (non-Finnish) · 86/1,179,972 alleles

Filtering AF 0.00604% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00557%

Overall 0.00582% 94/1,613,908 alleles · very rare exomes 83/1,461,786 · genomes 11/152,122 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00729%	13,721
Admixed American	0.005%	19,995
African / African-American	0.00401%	24,967
Remaining individualsnot grpmax-eligible	0.0032%	31,241

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.Pro57Ala
Coding: c.169C>G
MANE Select: NM_001375462
dbSNP: rs145658316
Type: single nucleotide variant
Location: chr3:188406289 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 57: 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-pro57ala (accessed [today's date]).

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