Is PLD1 p.Arg440Pro (c.1319G>C) pathogenic?

PLD1 p.Arg440Pro (c.1319G>C) is classified Uncertain significance in PLD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-04). AlphaMissense: likely pathogenic (0.6806); Very rare (popmax 0.00451%, eas).

How common is PLD1 p.Arg440Pro (c.1319G>C) in the general population?

PLD1 p.Arg440Pro (c.1319G>C) is very rare (popmax 0.00451%, eas) (gnomAD).

What do computational predictors say about PLD1 p.Arg440Pro (c.1319G>C)?

AlphaMissense predicts likely pathogenic (score 0.6806) — an in-silico prediction, not a clinical call.

PLD1 p.Arg440Pro

c.1319G>C · rs146936145 · VCV1450383

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00451%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6806	likely pathogenic
REVEL	0.147	moderately benign-leaning
SaProt	LLR -11.79	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.099	GERP 1.4
Regional constraint	o/e 0.98	unconstrained · MANE · 135 kb · p 0.57 · regional, not allelic
Overall
CADD	16.88	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 0.00451% East Asian · 2/44,360 alleles

Filtering AF 0.000747% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00028%

Overall 0.000147% 2/1,362,354 alleles · very rare

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: PLD1
Protein: p.Arg440Pro
Coding: c.1319G>C
MANE Select: NM_002662
dbSNP: rs146936145
Type: single nucleotide variant
Location: chr3:171692351 (GRCh38)
Gene constraint: LOEUF 0.822 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.92 · 2 PDB
Residue 440: an α-helix

Full PLD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLD1 p.Arg440His Uncertain significance ★★ ⚠ same residue
PLD1 p.Arg440Gly Uncertain significance ★ ⚠ same residue
PLD1 c.2430-1G>A Pathogenic/Likely pathogenic ★★ same type
PLD1 c.2593+1G>A Pathogenic/Likely pathogenic ★★ same type
PLD1 p.Arg407Ter Pathogenic/Likely pathogenic ★★ same type
PLD1 p.Tyr894Ser Likely pathogenic ★★ same type
PLD1 p.Ala689Val Uncertain significance ★★ ⚠ same type
PLD1 p.Ala765Thr 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/pld1-p-arg440pro (accessed [today's date]).

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