Is PLIN1 p.Pro109Ala (c.325C>G) pathogenic?

PLIN1 p.Pro109Ala (c.325C>G) is classified Uncertain significance in PLIN1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-13). AlphaMissense: likely benign (0.2736); Ultra-rare (popmax 0.014%, eas).

How common is PLIN1 p.Pro109Ala (c.325C>G) in the general population?

PLIN1 p.Pro109Ala (c.325C>G) is ultra-rare (popmax 0.014%, eas) (gnomAD).

What do computational predictors say about PLIN1 p.Pro109Ala (c.325C>G)?

AlphaMissense predicts likely benign (score 0.2736) — an in-silico prediction, not a clinical call.

PLIN1 p.Pro109Ala

c.325C>G · rs768147408 · VCV3215230

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2736 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.014%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2736	likely benign
REVEL	0.149	moderately benign-leaning
SaProt	LLR -10.22	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 12 kb · p 0.026 · regional, not allelic
Overall
CADD	23.2	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 0.014% East Asian · 6/42,790 alleles

Filtering AF 0.00602% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00409%

Overall 0.0028% 44/1,569,512 alleles · ultra-rare exomes 38/1,417,306 · genomes 6/152,206 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0625%	1,600
East Asiangrpmax	0.014%	7,132
Remaining individualsnot grpmax-eligible	0.0115%	8,700
European (non-Finnish)	0.00112%	88,944

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro109Ala
Coding: c.325C>G
MANE Select: NM_002666
dbSNP: rs768147408
Type: single nucleotide variant
Location: chr15:89671490 (GRCh38)
Gene constraint: LOEUF 1.201 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 54.52

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

Similar variants

PLIN1 p.Pro109Leu Uncertain significance ★ ⚠ same residue
PLIN1 p.Pro109Thr 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

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-pro109ala (accessed [today's date]).

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