Is PLA2G4A p.Pro656Ser (c.1966C>T) pathogenic?

PLA2G4A p.Pro656Ser (c.1966C>T) is classified Uncertain significance in PLA2G4A (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-06). AlphaMissense: likely benign (0.1679); Ultra-rare (popmax 0.0165%, mid).

How common is PLA2G4A p.Pro656Ser (c.1966C>T) in the general population?

PLA2G4A p.Pro656Ser (c.1966C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PLA2G4A p.Pro656Ser (c.1966C>T)?

AlphaMissense predicts likely benign (score 0.1679) — an in-silico prediction, not a clinical call.

PLA2G4A p.Pro656Ser

c.1966C>T · VCV3419703

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1679 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1679	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -11.39	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.2, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 134 kb · p 2.6e-10 · regional, not allelic
Overall
CADD	21.4	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 0.0165% Middle Eastern · 1/6,078 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000559% 9/1,610,568 alleles · ultra-rare exomes 8/1,458,458 · genomes 1/152,110 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,078
Remaining individualsnot grpmax-eligible	0.00321%	31,175
European (non-Finnish)	0.00051%	196,161

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: PLA2G4A
Protein: p.Pro656Ser
Coding: c.1966C>T
MANE Select: NM_024420
Type: single nucleotide variant
Location: chr1:186979320 (GRCh38)
Gene constraint: LOEUF 0.89 · pLI 0.19 (gnomAD)
Structure: AlphaFold pLDDT 84.15 · 3 PDB
Residue 656: the pla2c domain

Full PLA2G4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLA2G4A p.Ala34Thr Uncertain significance ★★ ⚠ same type
PLA2G4A p.Ala364Thr Uncertain significance ★★ ⚠ same type
PLA2G4A p.Met209Thr Uncertain significance ★★ ⚠ same type
PLA2G4A p.Met468Val Uncertain significance ★★ ⚠ same type
PLA2G4A p.Met470Val Uncertain significance ★★ ⚠ same type
PLA2G4A c.115+13T>A Benign/Likely benign ★★ same type
PLA2G4A c.115+7G>A Likely benign ★★ same type
PLA2G4A c.1264+12A>T Likely benign ★★ 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/pla2g4a-p-pro656ser (accessed [today's date]).

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