Is LPP p.Ser259Pro (c.775T>C) pathogenic?

LPP p.Ser259Pro (c.775T>C) is classified Benign in LPP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-12-31). AlphaMissense: likely benign (0.0704); Low-frequency (popmax 4.96%, afr).

How common is LPP p.Ser259Pro (c.775T>C) in the general population?

LPP p.Ser259Pro (c.775T>C) is low-frequency (popmax 4.96%, afr) (gnomAD).

What do computational predictors say about LPP p.Ser259Pro (c.775T>C)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

LPP p.Ser259Pro

c.775T>C · rs35940579 · VCV785075

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 4.96%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -6.06	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 -0.4	GERP -1.4
Regional constraint	o/e 1.15	unconstrained · MANE · 468 kb · p 2.3e-05 · regional, not allelic
Overall
CADD	6.853	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 4.96% African / African-American · 3,716/74,966 alleles

Filtering AF 4.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.77%

Overall 0.258% 4,159/1,614,016 alleles · low-frequency exomes 2,051/1,461,876 · genomes 2,108/152,140 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	4.96%	20
Middle Eastern	0.33%	303
Admixed American	0.315%	318
Remaining individualsnot grpmax-eligible	0.28%	357
South Asian	0.011%	9,108
European (non-Finnish)	0.00415%	24,081

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.Ser259Pro
Coding: c.775T>C
MANE Select: NM_001375462
dbSNP: rs35940579
Type: single nucleotide variant
Location: chr3:188609506 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.99
Residue 259: a UniProt-annotated variant site (in)

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-ser259pro (accessed [today's date]).

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