Is PLOD3 p.Pro564Ser (c.1690C>T) pathogenic?

PLOD3 p.Pro564Ser (c.1690C>T) is classified Uncertain significance in PLOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-09). AlphaMissense: ambiguous (0.3731); Ultra-rare (popmax 0.0111%, eas).

How common is PLOD3 p.Pro564Ser (c.1690C>T) in the general population?

PLOD3 p.Pro564Ser (c.1690C>T) is ultra-rare (popmax 0.0111%, eas) (gnomAD).

What do computational predictors say about PLOD3 p.Pro564Ser (c.1690C>T)?

AlphaMissense predicts ambiguous (score 0.3731) — an in-silico prediction, not a clinical call.

PLOD3 p.Pro564Ser

c.1690C>T · rs757518820 · VCV1465299

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3731 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0111%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3731	ambiguous
REVEL	0.759	pathogenic-leaning
SaProt	LLR -8.19	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 4.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 1,452 bp · p 0.64 · regional, not allelic
Overall
CADD	29.5	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 0.0111% East Asian · 5/44,860 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00276%

Overall 0.000434% 7/1,612,044 alleles · ultra-rare exomes 6/1,459,862 · genomes 1/152,182 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0111%	8,972
Remaining individualsnot grpmax-eligible	0.00321%	31,200

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.Pro564Ser
Coding: c.1690C>T
MANE Select: NM_001084
dbSNP: rs757518820
Type: single nucleotide variant
Location: chr7:101208951 (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 564: 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.Pro564Leu Uncertain significance ★ ⚠ same residue
PLOD3 p.Pro564= Likely benign ★ 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-pro564ser (accessed [today's date]).

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