Is PPCS p.Leu280= (c.840A>G) pathogenic?

PPCS p.Leu280= (c.840A>G) is classified Benign/Likely benign in PPCS (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-31). Rare (popmax 0.33%, eas).

How common is PPCS p.Leu280= (c.840A>G) in the general population?

PPCS p.Leu280= (c.840A>G) is rare (popmax 0.33%, eas) (gnomAD).

PPCS p.Leu280=

c.840A>G · rs142078638 · VCV1599807

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

rare (popmax 0.33%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.86	GERP -4.6
Overall
CADD	1.419	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.33% East Asian · 148/44,882 alleles

Filtering AF 0.286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.27%

Overall 0.023% 372/1,614,194 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.33%	303
African / African-American	0.161%	620
South Asian	0.0417%	2,397
Remaining individualsnot grpmax-eligible	0.0416%	2,404
Admixed American	0.0117%	8,576
European (non-Finnish)	0.00271%	36,875

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: PPCS
Protein: p.Leu280=
Coding: c.840A>G
MANE Select: NM_024664
dbSNP: rs142078638
Type: single nucleotide variant
Location: chr1:42459830 (GRCh38)
Gene constraint: LOEUF 1.064 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.94 · 2 PDB

Full PPCS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPCS p.Ala162Pro Uncertain significance ★★ ⚠ same type
PPCS p.Pro107Ser Uncertain significance ★★ ⚠ same type
PPCS c.*91T>G Benign ★★ same type
PPCS p.Phe73= Likely benign ★★ same type
PPCS p.Ala8Ser Uncertain significance ★ ⚠ same type
PPCS p.Leu118Met Uncertain significance ★ ⚠ same type
PPCS p.Thr68Pro Uncertain significance ★ ⚠ same type
PPCS c.508+14G>C Likely 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/ppcs-p-leu280 (accessed [today's date]).

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