Is PLD4 p.Arg235Gln (c.704G>A) pathogenic?

PLD4 p.Arg235Gln (c.704G>A) is classified Uncertain significance in PLD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-09). AlphaMissense: likely benign (0.3145); Ultra-rare (popmax 0.0245%, eas).

How common is PLD4 p.Arg235Gln (c.704G>A) in the general population?

PLD4 p.Arg235Gln (c.704G>A) is ultra-rare (popmax 0.0245%, eas) (gnomAD).

What do computational predictors say about PLD4 p.Arg235Gln (c.704G>A)?

AlphaMissense predicts likely benign (score 0.3145) — an in-silico prediction, not a clinical call.

PLD4 p.Arg235Gln

c.704G>A · rs750793265 · VCV2370791

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3145 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.3145	likely benign
REVEL	0.37	indeterminate
SaProt	LLR -12.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,820 bp · p 0.021 · regional, not allelic
Overall
CADD	32.0	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 0.0245% East Asian · 11/44,888 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00291% 47/1,613,360 alleles · ultra-rare exomes 43/1,461,030 · genomes 4/152,330 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,081
South Asian	0.0165%	6,072
Remaining individualsnot grpmax-eligible	0.008%	12,499
Admixed American	0.00333%	30,011
African / African-American	0.00133%	75,044
European (non-Finnish)	0.0011%	90,766

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.Arg235Gln
Coding: c.704G>A
MANE Select: NM_138790
dbSNP: rs750793265
Type: single nucleotide variant
Location: chr14:104930092 (GRCh38)
Gene constraint: LOEUF 1.583 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 3 PDB
Residue 235: the pld phosphodiesterase 1 domain; an α-helix

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-arg235gln (accessed [today's date]).

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