Is PLIN1 p.Arg489Cys (c.1465C>T) pathogenic?

PLIN1 p.Arg489Cys (c.1465C>T) is classified Likely benign in PLIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: ambiguous (0.342); Ultra-rare (popmax 0.0945%, mid).

How common is PLIN1 p.Arg489Cys (c.1465C>T) in the general population?

PLIN1 p.Arg489Cys (c.1465C>T) is ultra-rare (popmax 0.0945%, mid) (gnomAD).

What do computational predictors say about PLIN1 p.Arg489Cys (c.1465C>T)?

AlphaMissense predicts ambiguous (score 0.342) — an in-silico prediction, not a clinical call.

PLIN1 p.Arg489Cys

c.1465C>T · VCV4926576

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.342 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0945%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.342	ambiguous
REVEL	0.113	moderately benign-leaning
SaProt	LLR -8.89	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 0.99, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 12 kb · p 0.026 · regional, not allelic
Overall
CADD	24.5	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 0.0945% Middle Eastern · 4/4,232 alleles

Filtering AF 0.0323% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0194%

Overall 0.00839% 124/1,477,772 alleles · ultra-rare exomes 115/1,326,298 · genomes 9/151,474 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0945%	1,058
South Asian	0.018%	5,560
Admixed American	0.0157%	6,375
Remaining individualsnot grpmax-eligible	0.00878%	11,385
European (non-Finnish)	0.00832%	12,021
East Asian	0.00287%	34,840

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.Arg489Cys
Coding: c.1465C>T
MANE Select: NM_002666
Type: single nucleotide variant
Location: chr15:89665687 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.52
Residue 489: the 'disordered' region

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

Similar variants

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
PLIN1 c.251-153G>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-arg489cys (accessed [today's date]).

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