Is PLD3 p.Ser391Pro (c.1171T>C) pathogenic?

PLD3 p.Ser391Pro (c.1171T>C) is classified Uncertain significance in PLD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-28). AlphaMissense: likely pathogenic (0.6248); Ultra-rare (popmax 0.0784%, amr).

How common is PLD3 p.Ser391Pro (c.1171T>C) in the general population?

PLD3 p.Ser391Pro (c.1171T>C) is ultra-rare (popmax 0.0784%, amr) (gnomAD).

What do computational predictors say about PLD3 p.Ser391Pro (c.1171T>C)?

AlphaMissense predicts likely pathogenic (score 0.6248) — an in-silico prediction, not a clinical call.

PLD3 p.Ser391Pro

c.1171T>C · rs780587128 · VCV2171288

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6248 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0784%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6248	likely pathogenic
REVEL	0.175	moderately benign-leaning
SaProt	LLR -11.53	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 1.1	GERP 0.45, phastCons 0.9
Regional constraint	o/e 0.90	unconstrained · MANE · 12 kb · p 0.012 · regional, not allelic
Overall
CADD	15.75	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 0.0784% Admixed American · 47/59,974 alleles

Filtering AF 0.0605% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0542%

Overall 0.003% 48/1,599,722 alleles · ultra-rare exomes 44/1,447,584 · genomes 4/152,138 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0784%	1,276
African / African-American	0.00134%	74,894

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: PLD3
Protein: p.Ser391Pro
Coding: c.1171T>C
MANE Select: NM_012268
dbSNP: rs780587128
Type: single nucleotide variant
Location: chr19:40376760 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.15 · 7 PDB
Residue 391: a β-strand

Full PLD3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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PLD3 p.Arg375Trp Uncertain significance ★★ ⚠ same type
PLD3 p.Arg413His Uncertain significance ★★ ⚠ same type
PLD3 p.Arg424Ser Uncertain significance ★★ ⚠ same type
PLD3 p.Arg457Gln Uncertain significance ★★ ⚠ same type
PLD3 p.Arg488His Uncertain significance ★★ ⚠ same type
PLD3 p.Asn313Asp Uncertain significance ★★ ⚠ same type
PLD3 p.Gln137Arg 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/pld3-p-ser391pro (accessed [today's date]).

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