Is PLA2G6 p.Pro641Ala (c.1921C>G) pathogenic?

PLA2G6 p.Pro641Ala (c.1921C>G) is classified Likely pathogenic in PLA2G6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-10). AlphaMissense: likely pathogenic (0.972); Very rare (popmax 8.53e-05%, nfe); Associated with congenital nervous system disorder.

What condition is associated with PLA2G6 p.Pro641Ala (c.1921C>G)?

PLA2G6 p.Pro641Ala (c.1921C>G) is associated with congenital nervous system disorder (ClinVar).

How common is PLA2G6 p.Pro641Ala (c.1921C>G) in the general population?

PLA2G6 p.Pro641Ala (c.1921C>G) is very rare (popmax 8.53e-05%, nfe) (gnomAD).

What do computational predictors say about PLA2G6 p.Pro641Ala (c.1921C>G)?

AlphaMissense predicts likely pathogenic (score 0.972) — an in-silico prediction, not a clinical call.

PLA2G6 p.Pro641Ala

c.1921C>G · rs2145682922 · VCV1180822

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.53e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital nervous system disorder

Computational evidence

Protein change
AlphaMissense	0.972	likely pathogenic ✓ concordant with ClinVar · top 10% in PLA2G6
REVEL	0.94	strongly pathogenic-leaning
SaProt	LLR -12.35	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.86	unconstrained · MANE · 57 kb · p 2e-06 · regional, not allelic
Overall
CADD	28.5	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 8.53e-05% European (non-Finnish) · 1/1,172,198 alleles

Overall 6.27e-05% 1/1,595,826 alleles · very rare exomes 1/1,443,554 · genomes 0/152,272 · joint denominator

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: PLA2G6
Protein: p.Pro641Ala
Coding: c.1921C>G
MANE Select: NM_003560
dbSNP: rs2145682922
Type: single nucleotide variant
Location: chr22:38115640 (GRCh38)
Gene constraint: LOEUF 0.972 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.16
Residue 641: the pnpla domain

Full PLA2G6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital nervous system disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PLA2G6 p.Pro641Ser Uncertain significance ★ ⚠ same residue
PLA2G6 p.Trp631Ter Pathogenic/Likely pathogenic ★★ same condition
PLA2G6 p.Gly490Asp Likely pathogenic ★ same condition
PLA2G6 p.Ala633Val Conflicting classifications of pathogenicity ★ ⚠ same condition
PLA2G6 p.Tyr790Ter Conflicting classifications of pathogenicity ★ same condition
PLA2G6 c.1078-1G>A Likely pathogenic ★★ same type
PLA2G6 c.1186+1G>A Pathogenic/Likely pathogenic ★★ same type
PLA2G6 c.1186+1G>T Pathogenic/Likely pathogenic ★★ 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/pla2g6-p-pro641ala (accessed [today's date]).

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