Is PLOD2 p.Ala291Val (c.872C>T) pathogenic?

PLOD2 p.Ala291Val (c.872C>T) is classified Uncertain significance in PLOD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-09). AlphaMissense: likely benign (0.0823); Very rare (popmax 0.00222%, nfe).

How common is PLOD2 p.Ala291Val (c.872C>T) in the general population?

PLOD2 p.Ala291Val (c.872C>T) is very rare (popmax 0.00222%, nfe) (gnomAD).

What do computational predictors say about PLOD2 p.Ala291Val (c.872C>T)?

AlphaMissense predicts likely benign (score 0.0823) — an in-silico prediction, not a clinical call.

PLOD2 p.Ala291Val

c.872C>T · rs748996197 · VCV1944159

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0823 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00222%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0823	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -6.48	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 2.8	GERP -1.3, phastCons 0.2
Regional constraint	o/e 0.99	unconstrained · MANE · 90 kb · p 0.85 · regional, not allelic
Overall
CADD	14.55	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 0.00222% European (non-Finnish) · 25/1,127,272 alleles

Filtering AF 0.00152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00129%

Overall 0.00174% 27/1,555,764 alleles · very rare exomes 25/1,403,996 · genomes 2/151,768 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00222%	45,091
Admixed American	0.00167%	59,858
Remaining individualsnot grpmax-eligible	0.00165%	60,474

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.Ala291Val
Coding: c.872C>T
MANE Select: NM_182943
dbSNP: rs748996197
Type: single nucleotide variant
Location: chr3:146091807 (GRCh38)
Gene constraint: LOEUF 1.209 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 92.63
Residue 291: a UniProt-annotated variant site (in brks2; likely pathogenic)

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

Similar variants

PLOD2 p.Ala291Ser Uncertain significance ★ ⚠ same residue
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

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-ala291val (accessed [today's date]).

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