Is PLOD3 p.Pro20Ala (c.58C>G) pathogenic?

PLOD3 p.Pro20Ala (c.58C>G) is classified Uncertain significance in PLOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). AlphaMissense: likely benign (0.0486); Ultra-rare (popmax 0.0102%, sas).

How common is PLOD3 p.Pro20Ala (c.58C>G) in the general population?

PLOD3 p.Pro20Ala (c.58C>G) is ultra-rare (popmax 0.0102%, sas) (gnomAD).

What do computational predictors say about PLOD3 p.Pro20Ala (c.58C>G)?

AlphaMissense predicts likely benign (score 0.0486) — an in-silico prediction, not a clinical call.

PLOD3 p.Pro20Ala

c.58C>G · rs1798292961 · VCV2785017

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0486 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0102%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0486	likely benign
REVEL	0.069	moderately benign-leaning
SaProt	LLR -5.38	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 3.1	GERP 3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 6,691 bp · p 0.12 · regional, not allelic
Overall
CADD	2.07	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 0.0102% South Asian · 8/78,546 alleles

Filtering AF 0.00507% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00365%

Overall 0.0006% 9/1,501,144 alleles · ultra-rare exomes 8/1,348,852 · genomes 1/152,292 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0102%	9,818
European (non-Finnish)	8.87e-05%	1,127,009

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: PLOD3
Protein: p.Pro20Ala
Coding: c.58C>G
MANE Select: NM_001084
dbSNP: rs1798292961
Type: single nucleotide variant
Location: chr7:101217217 (GRCh38)
Gene constraint: LOEUF 0.925 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.80 · 18 PDB

Full PLOD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLOD3 p.Pro20fs Pathogenic ★ same residue
PLOD3 c.1359-1G>C Likely pathogenic ★★ same type
PLOD3 p.Arg452Ter Pathogenic ★★ same type
PLOD3 p.Tyr630Ter Pathogenic/Likely pathogenic ★★ same type
PLOD3 c.338+6G>C Uncertain significance ★★ same type
PLOD3 p.Ala371Val Uncertain significance ★★ ⚠ same type
PLOD3 p.Ala431Thr Uncertain significance ★★ ⚠ same type
PLOD3 p.Ala59Val 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/plod3-p-pro20ala (accessed [today's date]).

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