Is PLD4 p.Arg347Pro (c.1040G>C) pathogenic?

PLD4 p.Arg347Pro (c.1040G>C) is classified Uncertain significance in PLD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-25). AlphaMissense: ambiguous (0.4994); Very rare (popmax 0.00333%, nfe).

How common is PLD4 p.Arg347Pro (c.1040G>C) in the general population?

PLD4 p.Arg347Pro (c.1040G>C) is very rare (popmax 0.00333%, nfe) (gnomAD).

What do computational predictors say about PLD4 p.Arg347Pro (c.1040G>C)?

AlphaMissense predicts ambiguous (score 0.4994) — an in-silico prediction, not a clinical call.

PLD4 p.Arg347Pro

c.1040G>C · rs372744359 · VCV2602303

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4994 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4994	ambiguous
REVEL	0.14	moderately benign-leaning
SaProt	LLR -10.04	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.2	GERP -4.3, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,820 bp · p 0.021 · regional, not allelic
Overall
CADD	24.2	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 0.00333% European (non-Finnish) · 38/1,141,254 alleles

Filtering AF 0.00247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00217%

Overall 0.00246% 38/1,542,858 alleles · very rare exomes 36/1,390,688 · genomes 2/152,170 · joint denominator

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: PLD4
Protein: p.Arg347Pro
Coding: c.1040G>C
MANE Select: NM_138790
dbSNP: rs372744359
Type: single nucleotide variant
Location: chr14:104931869 (GRCh38)
Gene constraint: LOEUF 1.583 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 3 PDB

Full PLD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLD4 c.468+4C>T Likely benign ★★ same type
PLD4 p.Ala109Val Uncertain significance ★ ⚠ same type
PLD4 p.Ala121Val Uncertain significance ★ ⚠ same type
PLD4 p.Ala177Thr Uncertain significance ★ ⚠ same type
PLD4 p.Ala195Thr Uncertain significance ★ ⚠ same type
PLD4 p.Ala245Thr Uncertain significance ★ ⚠ same type
PLD4 p.Ala307Glu Uncertain significance ★ ⚠ same type
PLD4 p.Ala326Val 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/pld4-p-arg347pro (accessed [today's date]).

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