Is PLOD3 p.Arg647Pro (c.1940G>C) pathogenic?

PLOD3 p.Arg647Pro (c.1940G>C) is classified Uncertain significance in PLOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely pathogenic (0.8262); Very rare (popmax 0.00272%, afr).

How common is PLOD3 p.Arg647Pro (c.1940G>C) in the general population?

PLOD3 p.Arg647Pro (c.1940G>C) is very rare (popmax 0.00272%, afr) (gnomAD).

What do computational predictors say about PLOD3 p.Arg647Pro (c.1940G>C)?

AlphaMissense predicts likely pathogenic (score 0.8262) — an in-silico prediction, not a clinical call.

PLOD3 p.Arg647Pro

c.1940G>C · VCV3674348

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8262 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8262	likely pathogenic
REVEL	0.387	indeterminate
SaProt	LLR -10.81	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>T here scores Δ0.36 · evaluated, not missing
Constraint at this position
Conservation	phyloP 5.8	GERP 0.35, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,605 bp · p 0.91 · regional, not allelic
Overall
CADD	21.8	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 0.00272% African / African-American · 2/73,514 alleles

Filtering AF 0.000451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000169%

Overall 0.000321% 5/1,556,532 alleles · very rare exomes 4/1,404,516 · genomes 1/152,016 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00272%	36,757
Remaining individualsnot grpmax-eligible	0.00166%	60,306
European (non-Finnish)	0.000174%	574,838

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.Arg647Pro
Coding: c.1940G>C
MANE Select: NM_001084
Type: single nucleotide variant
Location: chr7:101206900 (GRCh38)
Gene constraint: LOEUF 0.925 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 91.80 · 18 PDB
Residue 647: the fe2og dioxygenase domain; a UniProt-annotated variant site (in bcard; uncertain significance)

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

Similar variants

PLOD3 p.Arg647Gln Uncertain significance ★★ ⚠ same residue
PLOD3 p.Arg647Trp Uncertain significance ★ ⚠ 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

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-arg647pro (accessed [today's date]).

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