Is PLIN5 p.Ala175Pro (c.523G>C) pathogenic?

PLIN5 p.Ala175Pro (c.523G>C) is classified Uncertain significance in PLIN5 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-02). AlphaMissense: ambiguous (0.5385); Ultra-rare (popmax 0.0167%, amr).

How common is PLIN5 p.Ala175Pro (c.523G>C) in the general population?

PLIN5 p.Ala175Pro (c.523G>C) is ultra-rare (popmax 0.0167%, amr) (gnomAD).

What do computational predictors say about PLIN5 p.Ala175Pro (c.523G>C)?

AlphaMissense predicts ambiguous (score 0.5385) — an in-silico prediction, not a clinical call.

PLIN5 p.Ala175Pro

c.523G>C · VCV3420867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5385 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5385	ambiguous
REVEL	0.061	moderately benign-leaning
SaProt	LLR -11.58	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.49	GERP 0.42, phastCons 0.004
Regional constraint	o/e 1.08	unconstrained · MANE · 11 kb · p 0.045 · regional, not allelic
Overall
CADD	20.4	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 0.0167% Admixed American · 10/59,738 alleles

Filtering AF 0.00903% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00684%

Overall 0.000621% 10/1,611,218 alleles · ultra-rare exomes 6/1,459,130 · genomes 4/152,088 · 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: PLIN5
Protein: p.Ala175Pro
Coding: c.523G>C
MANE Select: NM_001013706
Type: single nucleotide variant
Location: chr19:4525830 (GRCh38)
Gene constraint: LOEUF 1.525 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 66.54

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

Similar variants

PLIN5 p.Pro452Leu Uncertain significance ★★ ⚠ same type
PLIN5 p.Ala174Val 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
PLIN5 p.Ala341Val Uncertain significance ★ ⚠ same type
PLIN5 p.Ala356Ser Uncertain significance ★ ⚠ same type
PLIN5 p.Ala356Thr 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-ala175pro (accessed [today's date]).

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