Is PLIN3 p.Ser138Arg (c.414C>A) pathogenic?

PLIN3 p.Ser138Arg (c.414C>A) is classified Uncertain significance in PLIN3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). AlphaMissense: likely benign (0.2279); Very rare (popmax 0.00263%, nfe).

How common is PLIN3 p.Ser138Arg (c.414C>A) in the general population?

PLIN3 p.Ser138Arg (c.414C>A) is very rare (popmax 0.00263%, nfe) (gnomAD).

What do computational predictors say about PLIN3 p.Ser138Arg (c.414C>A)?

AlphaMissense predicts likely benign (score 0.2279) — an in-silico prediction, not a clinical call.

PLIN3 p.Ser138Arg

c.414C>A · VCV4139692

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2279 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00263%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2279	likely benign
REVEL	0.11	moderately benign-leaning
SaProt	LLR -8.67	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -3.7	GERP -4.9
Regional constraint	o/e 1.01	unconstrained · MANE · 22 kb · p 0.8 · regional, not allelic
Overall
CADD	1.768	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00263% European (non-Finnish) · 31/1,180,004 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00193% 31/1,609,598 alleles · very rare exomes 24/1,457,410 · genomes 7/152,188 · joint denominator

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: PLIN3
Protein: p.Ser138Arg
Coding: c.414C>A
MANE Select: NM_005817
Type: single nucleotide variant
Location: chr19:4852236 (GRCh38)
Gene constraint: LOEUF 1.213 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.04

Full PLIN3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLIN3 p.Lys102= Benign ★★ same type
PLIN3 p.Ala139Thr Uncertain significance ★ ⚠ same type
PLIN3 p.Ala212Val Uncertain significance ★ ⚠ same type
PLIN3 p.Ala215Thr Uncertain significance ★ ⚠ same type
PLIN3 p.Ala371Ser Uncertain significance ★ ⚠ same type
PLIN3 p.Ala397Thr Uncertain significance ★ ⚠ same type
PLIN3 p.Ala397Val Uncertain significance ★ ⚠ same type
PLIN3 p.Ala62Thr 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/plin3-p-ser138arg (accessed [today's date]).

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