Is PLOD3 p.Ser3Phe (c.8C>T) pathogenic?

PLOD3 p.Ser3Phe (c.8C>T) is classified Uncertain significance in PLOD3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-07). AlphaMissense: likely benign (0.0876); Ultra-rare (popmax 0.0899%, mid); Associated with Inborn genetic diseases.

What condition is associated with PLOD3 p.Ser3Phe (c.8C>T)?

PLOD3 p.Ser3Phe (c.8C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PLOD3 p.Ser3Phe (c.8C>T) in the general population?

PLOD3 p.Ser3Phe (c.8C>T) is ultra-rare (popmax 0.0899%, mid) (gnomAD).

What do computational predictors say about PLOD3 p.Ser3Phe (c.8C>T)?

AlphaMissense predicts likely benign (score 0.0876) — an in-silico prediction, not a clinical call.

PLOD3 p.Ser3Phe

c.8C>T · VCV3934582

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0876 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0899%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0876	likely benign
REVEL	0.064	moderately benign-leaning
SaProt	LLR -8.03	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.48	GERP -0.81, phastCons 0.001
Regional constraint	o/e 1.06	unconstrained · MANE · 6,691 bp · p 0.12 · regional, not allelic
Overall
CADD	15.55	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 0.0899% Middle Eastern · 5/5,562 alleles

Filtering AF 0.0353% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0259%

Overall 0.00451% 67/1,487,162 alleles · ultra-rare exomes 56/1,334,852 · genomes 11/152,310 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0899%	1,112
African / African-American	0.0419%	2,384
Remaining individualsnot grpmax-eligible	0.0385%	2,599
Admixed American	0.0171%	5,860
East Asian	0.0053%	18,878
South Asian	0.00131%	76,280
European (non-Finnish)	8.93e-05%	1,119,695

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.Ser3Phe
Coding: c.8C>T
MANE Select: NM_001084
Type: single nucleotide variant
Location: chr7:101217267 (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

Disease context

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

Similar variants

PLOD3 p.Ser3Tyr 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-ser3phe (accessed [today's date]).

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