Is PLD2 p.Arg336Pro (c.1007G>C) pathogenic?

PLD2 p.Arg336Pro (c.1007G>C) is classified Uncertain significance in PLD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-14). AlphaMissense: likely pathogenic (0.7895); Ultra-rare (popmax 0.0253%, sas).

How common is PLD2 p.Arg336Pro (c.1007G>C) in the general population?

PLD2 p.Arg336Pro (c.1007G>C) is ultra-rare (popmax 0.0253%, sas) (gnomAD).

What do computational predictors say about PLD2 p.Arg336Pro (c.1007G>C)?

AlphaMissense predicts likely pathogenic (score 0.7895) — an in-silico prediction, not a clinical call.

PLD2 p.Arg336Pro

c.1007G>C · VCV3307412

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7895 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, sas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7895	likely pathogenic
REVEL	0.242	benign-leaning
SaProt	LLR -11.89	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 2.6	GERP -0.29, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 15 kb · p 0.073 · regional, not allelic
Overall
CADD	22.1	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 0.0253% South Asian · 23/90,786 alleles

Filtering AF 0.0172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0146%

Overall 0.00162% 26/1,608,454 alleles · ultra-rare exomes 25/1,456,314 · genomes 1/152,140 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0253%	3,947
Remaining individualsnot grpmax-eligible	0.00481%	20,791

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: PLD2
Protein: p.Arg336Pro
Coding: c.1007G>C
MANE Select: NM_002663
Type: single nucleotide variant
Location: chr17:4810948 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.55 · 6 PDB
Residue 336: a β-strand

Full PLD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLD2 p.Arg336Gln Uncertain significance ★ ⚠ same residue
PLD2 p.Arg336Trp Uncertain significance ★ ⚠ same residue
PLD2 p.Arg336= Likely benign ★ same residue
PLD2 c.2010-9C>T Benign ★★ same type
PLD2 p.Arg330Gln Benign ★★ ⚠ same type
PLD2 p.Arg490Cys Likely benign ★★ same type
PLD2 p.Arg553Gln Benign ★★ ⚠ same type
PLD2 p.His278Tyr Benign ★★ 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/pld2-p-arg336pro (accessed [today's date]).

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