Is PLCG2 p.Ala136= (c.408G>A) pathogenic?

PLCG2 p.Ala136= (c.408G>A) is classified Uncertain significance in PLCG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-07). Very rare (popmax 0.00445%, eas).

How common is PLCG2 p.Ala136= (c.408G>A) in the general population?

PLCG2 p.Ala136= (c.408G>A) is very rare (popmax 0.00445%, eas) (gnomAD).

PLCG2 p.Ala136=

c.408G>A · VCV4931502

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -20	GERP -3.4
Overall
CADD	0.413	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,896 alleles

Filtering AF 0.000738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000276%

Overall 0.00062% 10/1,613,268 alleles · very rare exomes 9/1,461,132 · genomes 1/152,136 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00469%	21,341
East Asiangrpmax	0.00445%	22,448
South Asian	0.0022%	45,532
European (non-Finnish)	0.000254%	393,123

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: PLCG2
Protein: p.Ala136=
Coding: c.408G>A
MANE Select: NM_002661
Type: single nucleotide variant
Location: chr16:81858333 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.49 · 8 PDB

Full PLCG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PLCG2 p.Ala136Thr Uncertain significance ★★ ⚠ same residue
PLCG2 p.Ala136Val Uncertain significance ★★ ⚠ same residue
PLCG2 p.Ala708Pro Pathogenic ★★ ⚠ same type
PLCG2 c.1467+3G>A Uncertain significance ★★ same type
PLCG2 c.1934+1G>A Uncertain significance ★★ same type
PLCG2 c.2235+3A>G Uncertain significance ★★ same type
PLCG2 c.2235+5G>A Uncertain significance ★★ same type
PLCG2 c.2307+4C>T 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/plcg2-p-ala136 (accessed [today's date]).

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