Is PLD2 p.Arg464His (c.1391G>A) pathogenic?

PLD2 p.Arg464His (c.1391G>A) is classified Uncertain significance in PLD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-07). AlphaMissense: likely pathogenic (0.958); Ultra-rare (popmax 0.0164%, mid).

How common is PLD2 p.Arg464His (c.1391G>A) in the general population?

PLD2 p.Arg464His (c.1391G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about PLD2 p.Arg464His (c.1391G>A)?

AlphaMissense predicts likely pathogenic (score 0.958) — an in-silico prediction, not a clinical call.

PLD2 p.Arg464His

c.1391G>A · rs756122541 · VCV2516939

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.958 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.958	likely pathogenic
REVEL	0.678	pathogenic-leaning
SaProt	LLR -14.73	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.78, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 15 kb · p 0.073 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00149% 24/1,613,984 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
East Asian	0.00891%	11,220
Admixed American	0.00333%	29,989
Remaining individualsnot grpmax-eligible	0.0032%	31,244
South Asian	0.0022%	45,545
European (non-Finnish)	0.0011%	90,770

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.Arg464His
Coding: c.1391G>A
MANE Select: NM_002663
dbSNP: rs756122541
Type: single nucleotide variant
Location: chr17:4815870 (GRCh38)
Gene constraint: LOEUF 0.933 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 89.55 · 6 PDB
Residue 464: the pld phosphodiesterase 1 domain; the 'catalytic' region

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

Similar variants

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
PLD2 p.Ile860= Benign ★★ same type
PLD2 p.Thr569Ala Likely benign ★★ same type
PLD2 p.Ala184Val 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/pld2-p-arg464his (accessed [today's date]).

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