Is PLD3 p.Pro76Ala (c.226C>G) pathogenic?

PLD3 p.Pro76Ala (c.226C>G) is classified Benign/Likely benign in PLD3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0632); Rare (popmax 0.133%, mid).

How common is PLD3 p.Pro76Ala (c.226C>G) in the general population?

PLD3 p.Pro76Ala (c.226C>G) is rare (popmax 0.133%, mid) (gnomAD).

What do computational predictors say about PLD3 p.Pro76Ala (c.226C>G)?

AlphaMissense predicts likely benign (score 0.0632) — an in-silico prediction, not a clinical call.

PLD3 p.Pro76Ala

c.226C>G · rs138674695 · VCV2055115

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0632 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.133%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0632	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -5.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 12 kb · p 0.012 · regional, not allelic
Overall
CADD	22.8	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 0.133% Middle Eastern · 8/6,022 alleles

Filtering AF 0.066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.06%

Overall 0.0759% 1,222/1,610,478 alleles · rare exomes 1,086/1,458,176 · genomes 136/152,302 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.596%	168
Middle Easterngrpmax	0.133%	753
European (non-Finnish)	0.0654%	1,530
Ashkenazi Jewishnot grpmax-eligible	0.065%	1,539
Remaining individualsnot grpmax-eligible	0.0369%	2,709
African / African-American	0.012%	8,330
South Asian	0.00994%	10,063
Admixed American	0.0067%	14,925

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro76Ala
Coding: c.226C>G
MANE Select: NM_012268
dbSNP: rs138674695
Type: single nucleotide variant
Location: chr19:40366896 (GRCh38)
Gene constraint: LOEUF 0.727 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.15 · 7 PDB
Residue 76: a UniProt-annotated variant site (in); an α-helix

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

Similar variants

PLD3 p.Ala114Val Uncertain significance ★★ ⚠ same type
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-pro76ala (accessed [today's date]).

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