Is PLIN1 p.Arg519Pro (c.1556G>C) pathogenic?

PLIN1 p.Arg519Pro (c.1556G>C) is classified Uncertain significance in PLIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-07-07). AlphaMissense: ambiguous (0.4298); Ultra-rare (popmax 0.026%, nfe).

How common is PLIN1 p.Arg519Pro (c.1556G>C) in the general population?

PLIN1 p.Arg519Pro (c.1556G>C) is ultra-rare (popmax 0.026%, nfe) (gnomAD).

What do computational predictors say about PLIN1 p.Arg519Pro (c.1556G>C)?

AlphaMissense predicts ambiguous (score 0.4298) — an in-silico prediction, not a clinical call.

PLIN1 p.Arg519Pro

c.1556G>C · rs746427650 · VCV1338236

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4298 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.026%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4298	ambiguous
REVEL	0.136	moderately benign-leaning
SaProt	LLR -6.44	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 5.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 12 kb · p 0.026 · regional, not allelic
Overall
CADD	28.4	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 0.026% European (non-Finnish) · 296/1,138,986 alleles

Filtering AF 0.0235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0225%

Overall 0.02% 306/1,527,004 alleles · ultra-rare exomes 286/1,375,448 · genomes 20/151,556 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.026%	3,848
Remaining individualsnot grpmax-eligible	0.0136%	7,379
Admixed American	0.00199%	50,232
African / African-American	0.00139%	71,708

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: PLIN1
Protein: p.Arg519Pro
Coding: c.1556G>C
MANE Select: NM_002666
dbSNP: rs746427650
Type: single nucleotide variant
Location: chr15:89665596 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.52
Residue 519: the 'disordered' region

Full PLIN1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLIN1 p.Arg519Leu Uncertain significance ★ ⚠ same residue
PLIN1 p.Ala361Glu Uncertain significance ★★ ⚠ same type
PLIN1 p.Arg125Cys Uncertain significance ★★ ⚠ same type
PLIN1 p.Glu151Lys Uncertain significance ★★ ⚠ same type
PLIN1 p.Leu404Phe Uncertain significance ★★ ⚠ same type
PLIN1 p.Leu90Pro Uncertain significance ★★ ⚠ same type
PLIN1 p.Thr345Ala Uncertain significance ★★ ⚠ same type
PLIN1 c.1209+9C>T 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/plin1-p-arg519pro (accessed [today's date]).

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