Is PLOD3 p.Ser734Phe (c.2201C>T) pathogenic?

PLOD3 p.Ser734Phe (c.2201C>T) is classified Uncertain significance in PLOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely pathogenic (0.9972); Very rare (popmax 0.00237%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PLOD3 p.Ser734Phe (c.2201C>T)?

PLOD3 p.Ser734Phe (c.2201C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PLOD3 p.Ser734Phe (c.2201C>T) in the general population?

PLOD3 p.Ser734Phe (c.2201C>T) is very rare (popmax 0.00237%, nfe) (gnomAD).

What do computational predictors say about PLOD3 p.Ser734Phe (c.2201C>T)?

AlphaMissense predicts likely pathogenic (score 0.9972) — an in-silico prediction, not a clinical call.

PLOD3 p.Ser734Phe

c.2201C>T · rs1357311807 · VCV3215357

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9972	likely pathogenic · top 2% in PLOD3
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -16.11	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.2, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 2,605 bp · p 0.91 · regional, not allelic
Overall
CADD	33.0	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 0.00237% European (non-Finnish) · 28/1,179,958 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00186% 30/1,613,862 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,236
European (non-Finnish)grpmax	0.00237%	42,141

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser734Phe
Coding: c.2201C>T
MANE Select: NM_001084
dbSNP: rs1357311807
Type: single nucleotide variant
Location: chr7:101206297 (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 734: a β-strand; 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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLOD3 p.Ser734Thr Uncertain significance ★★ ⚠ same residue
PLOD3 c.338+6G>C Uncertain significance ★★ same condition
PLOD3 p.Ala59Val Uncertain significance ★★ ⚠ same condition
PLOD3 p.Ala646Val Uncertain significance ★★ ⚠ same condition
PLOD3 p.Arg135His Uncertain significance ★★ ⚠ same condition
PLOD3 p.Arg181His Uncertain significance ★★ ⚠ same condition
PLOD3 p.Arg313His Uncertain significance ★★ ⚠ same condition
PLOD3 p.Arg317Gln Uncertain significance ★★ ⚠ same condition

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-ser734phe (accessed [today's date]).

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