Is PLD4 p.Ala331Ser (c.991G>T) pathogenic?

PLD4 p.Ala331Ser (c.991G>T) is classified Uncertain significance in PLD4 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-20). AlphaMissense: likely benign (0.1409); Very rare (popmax 0.00182%, amr).

How common is PLD4 p.Ala331Ser (c.991G>T) in the general population?

PLD4 p.Ala331Ser (c.991G>T) is very rare (popmax 0.00182%, amr) (gnomAD).

What do computational predictors say about PLD4 p.Ala331Ser (c.991G>T)?

AlphaMissense predicts likely benign (score 0.1409) — an in-silico prediction, not a clinical call.

PLD4 p.Ala331Ser

c.991G>T · VCV3420223

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1409 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00182%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1409	likely benign
REVEL	0.458	indeterminate
SaProt	LLR -8.63	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 1.09	unconstrained · MANE · 5,820 bp · p 0.021 · regional, not allelic
Overall
CADD	25.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00182% Admixed American · 1/54,962 alleles

Filtering AF 6.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000318% 5/1,573,972 alleles · very rare exomes 4/1,421,798 · genomes 1/152,174 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00182%	54,962
African / African-American	0.00135%	73,878
European (non-Finnish)	0.000259%	386,376

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.Ala331Ser
Coding: c.991G>T
MANE Select: NM_138790
Type: single nucleotide variant
Location: chr14:104931820 (GRCh38)
Gene constraint: LOEUF 1.583 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.12 · 3 PDB

Full PLD4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLD4 p.Ala331Thr Uncertain significance ★ ⚠ same residue
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

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-ala331ser (accessed [today's date]).

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