Is PLOD2 p.Ile84Ser (c.251T>G) pathogenic?

PLOD2 p.Ile84Ser (c.251T>G) is classified Uncertain significance in PLOD2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-08-16). AlphaMissense: ambiguous (0.407); Ultra-rare (popmax 0.0312%, eas).

How common is PLOD2 p.Ile84Ser (c.251T>G) in the general population?

PLOD2 p.Ile84Ser (c.251T>G) is ultra-rare (popmax 0.0312%, eas) (gnomAD).

What do computational predictors say about PLOD2 p.Ile84Ser (c.251T>G)?

AlphaMissense predicts ambiguous (score 0.407) — an in-silico prediction, not a clinical call.

PLOD2 p.Ile84Ser

c.251T>G · rs369085322 · VCV1465931

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.407 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0312%, eas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.407	ambiguous
REVEL	0.165	moderately benign-leaning
SaProt	LLR -7.22	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 90 kb · p 0.85 · regional, not allelic
Overall
CADD	24.2	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 0.0312% East Asian · 14/44,806 alleles

Filtering AF 0.0189% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0151%

Overall 0.00087% 14/1,608,782 alleles · ultra-rare exomes 9/1,456,626 · genomes 5/152,156 · joint denominator

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: PLOD2
Protein: p.Ile84Ser
Coding: c.251T>G
MANE Select: NM_182943
dbSNP: rs369085322
Type: single nucleotide variant
Location: chr3:146121199 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63

Full PLOD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLOD2 c.1500+1G>T Pathogenic/Likely pathogenic ★★ same type
PLOD2 p.Arg440Ter Pathogenic/Likely pathogenic ★★ same type
PLOD2 p.Arg473Ter Pathogenic ★★ same type
PLOD2 p.Arg495Ter Pathogenic/Likely pathogenic ★★ same type
PLOD2 p.Arg680Ter Pathogenic/Likely pathogenic ★★ same type
PLOD2 c.1232+5T>A Uncertain significance ★★ same type
PLOD2 c.-170C>G Uncertain significance ★★ same type
PLOD2 p.Ala415Val 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/plod2-p-ile84ser (accessed [today's date]).

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