Is PLD1 p.His442Pro (c.1325A>C) pathogenic?

PLD1 p.His442Pro (c.1325A>C) is classified Pathogenic in PLD1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-09-30). AlphaMissense: likely pathogenic (0.6989); Absent from gnomAD v4.1; Associated with cardiac valvular defect, developmental.

What condition is associated with PLD1 p.His442Pro (c.1325A>C)?

PLD1 p.His442Pro (c.1325A>C) is associated with cardiac valvular defect, developmental (ClinVar).

How common is PLD1 p.His442Pro (c.1325A>C) in the general population?

PLD1 p.His442Pro (c.1325A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PLD1 p.His442Pro (c.1325A>C)?

AlphaMissense predicts likely pathogenic (score 0.6989) — an in-silico prediction, not a clinical call.

PLD1 p.His442Pro

c.1325A>C · rs769669104 · VCV426089

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6989 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiac valvular defect, developmental

Computational evidence

Protein change
AlphaMissense	0.6989	likely pathogenic ✓ concordant with ClinVar
REVEL	0.664	pathogenic-leaning
SaProt	LLR -15.20	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 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 135 kb · p 0.57 · regional, not allelic
Overall
CADD	26.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PLD1
Protein: p.His442Pro
Coding: c.1325A>C
MANE Select: NM_002662
dbSNP: rs769669104
Type: single nucleotide variant
Location: chr3:171692345 (GRCh38)
Gene constraint: LOEUF 0.822 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.92 · 2 PDB
Residue 442: a UniProt-annotated variant site (in cvdp1)

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 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
PLD1 p.Ala622Ser Benign ★★ 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-his442pro (accessed [today's date]).

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