Is PLD1 p.Val468Asp (c.1403T>A) pathogenic?

PLD1 p.Val468Asp (c.1403T>A) is classified Likely pathogenic in PLD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-29). AlphaMissense: likely pathogenic (0.9922); Ultra-rare (popmax 0.0117%, amr); Associated with cardiac valvular defect, developmental.

What condition is associated with PLD1 p.Val468Asp (c.1403T>A)?

PLD1 p.Val468Asp (c.1403T>A) is associated with cardiac valvular defect, developmental (ClinVar).

How common is PLD1 p.Val468Asp (c.1403T>A) in the general population?

PLD1 p.Val468Asp (c.1403T>A) is ultra-rare (popmax 0.0117%, amr) (gnomAD).

What do computational predictors say about PLD1 p.Val468Asp (c.1403T>A)?

AlphaMissense predicts likely pathogenic (score 0.9922) — an in-silico prediction, not a clinical call.

PLD1 p.Val468Asp

c.1403T>A · rs374719323 · VCV2582520

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9922 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0117%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cardiac valvular defect, developmental

Computational evidence

Protein change
AlphaMissense	0.9922	likely pathogenic ✓ concordant with ClinVar · top 5% in PLD1
REVEL	0.632	indeterminate
SaProt	LLR -15.39	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 135 kb · p 0.57 · regional, not allelic
Overall
CADD	27.6	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 0.0117% Admixed American · 7/60,000 alleles

Filtering AF 0.00543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0038%

Overall 0.00428% 69/1,614,032 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0117%	8,571
Remaining individualsnot grpmax-eligible	0.0064%	15,622
European (non-Finnish)	0.00492%	20,345

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.Val468Asp
Coding: c.1403T>A
MANE Select: NM_002662
dbSNP: rs374719323
Type: single nucleotide variant
Location: chr3:171688812 (GRCh38)
Gene constraint: LOEUF 0.822 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.92 · 2 PDB
Residue 468: the pld phosphodiesterase 1 domain; a β-strand; the 'catalytic' region

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

Disease context

cardiac valvular defect, developmental — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLD1 p.Val468= Likely benign ★★ same residue
PLD1 c.2593+1G>A Pathogenic/Likely pathogenic ★★ same condition
PLD1 p.Arg407Ter Pathogenic/Likely pathogenic ★★ same condition
PLD1 p.Arg298Gln Uncertain significance ★★ ⚠ same condition
PLD1 p.Arg440His Uncertain significance ★★ ⚠ same condition
PLD1 p.Asp661Val Uncertain significance ★★ ⚠ same condition
PLD1 p.Gly834Ser Uncertain significance ★★ ⚠ same condition
PLD1 p.Tyr894Cys Uncertain significance ★★ ⚠ same condition

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-val468asp (accessed [today's date]).

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