Is PLIN5 p.Arg25Pro (c.74G>C) pathogenic?

PLIN5 p.Arg25Pro (c.74G>C) is classified Uncertain significance in PLIN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-12). AlphaMissense: likely pathogenic (0.906); Very rare (popmax 0.00471%, eas).

How common is PLIN5 p.Arg25Pro (c.74G>C) in the general population?

PLIN5 p.Arg25Pro (c.74G>C) is very rare (popmax 0.00471%, eas) (gnomAD).

What do computational predictors say about PLIN5 p.Arg25Pro (c.74G>C)?

AlphaMissense predicts likely pathogenic (score 0.906) — an in-silico prediction, not a clinical call.

PLIN5 p.Arg25Pro

c.74G>C · VCV3934514

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.906 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00471%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.906	likely pathogenic · top 1% in PLIN5
REVEL	0.413	indeterminate
SaProt	LLR -14.64	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 11 kb · p 0.045 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00471% East Asian · 2/42,438 alleles

Filtering AF 0.000781% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000292%

Overall 0.000192% 3/1,559,458 alleles · very rare exomes 2/1,407,186 · genomes 1/152,272 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00471%	21,219
Remaining individualsnot grpmax-eligible	0.00166%	60,268

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: PLIN5
Protein: p.Arg25Pro
Coding: c.74G>C
MANE Select: NM_001013706
Type: single nucleotide variant
Location: chr19:4531809 (GRCh38)
Gene constraint: LOEUF 1.525 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.54
Residue 25: the 'essential for lipid droplet targeting' region; the 'interaction with lipe' region

Full PLIN5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLIN5 p.Arg25Cys Uncertain significance ★ same residue
PLIN5 p.Arg25His Uncertain significance ★ ⚠ same residue
PLIN5 p.Pro452Leu Uncertain significance ★★ ⚠ same type
PLIN5 p.Ala174Val Uncertain significance ★ ⚠ same type
PLIN5 p.Ala175Pro Uncertain significance ★ ⚠ same type
PLIN5 p.Ala232Thr Uncertain significance ★ ⚠ same type
PLIN5 p.Ala232Val Uncertain significance ★ ⚠ same type
PLIN5 p.Ala310Thr 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/plin5-p-arg25pro (accessed [today's date]).

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