Is PLA2R1 p.Ile1326Val (c.3976A>G) pathogenic?

PLA2R1 p.Ile1326Val (c.3976A>G) is classified Uncertain significance in PLA2R1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0616); Very rare (popmax 0.00111%, sas).

How common is PLA2R1 p.Ile1326Val (c.3976A>G) in the general population?

PLA2R1 p.Ile1326Val (c.3976A>G) is very rare (popmax 0.00111%, sas) (gnomAD).

What do computational predictors say about PLA2R1 p.Ile1326Val (c.3976A>G)?

AlphaMissense predicts likely benign (score 0.0616) — an in-silico prediction, not a clinical call.

PLA2R1 p.Ile1326Val

c.3976A>G · VCV4138389

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0616 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00111%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0616	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -4.05	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 -0.33	GERP -5, phastCons 0.005
Regional constraint	o/e 0.92	unconstrained · MANE · 121 kb · p 0.00097 · regional, not allelic
Overall
CADD	5.236	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 0.00111% South Asian · 1/89,772 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000206% 3/1,454,308 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00111%	89,772
European (non-Finnish)	0.00017%	587,762

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: PLA2R1
Protein: p.Ile1326Val
Coding: c.3976A>G
MANE Select: NM_007366
Type: single nucleotide variant
Location: chr2:159945074 (GRCh38)
Gene constraint: LOEUF 1 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.16 · 2 PDB
Residue 1326: the c-type lectin 8 domain; a β-strand; a disulfide bond

Full PLA2R1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLA2R1 p.Ile1326Leu Uncertain significance ★ ⚠ same residue
PLA2R1 p.Ile1326Thr Uncertain significance ★ ⚠ same residue
PLA2R1 p.Pro29Arg Uncertain significance ★★ ⚠ same type
PLA2R1 p.Leu294= Likely benign ★★ same type
PLA2R1 p.Ala1000Thr Uncertain significance ★ ⚠ same type
PLA2R1 p.Ala1068Thr Uncertain significance ★ ⚠ same type
PLA2R1 p.Ala1212Val Uncertain significance ★ ⚠ same type
PLA2R1 p.Ala133Val 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/pla2r1-p-ile1326val (accessed [today's date]).

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