Is AGAP2 p.Leu321Val (c.961C>G) pathogenic?

AGAP2 p.Leu321Val (c.961C>G) is classified Uncertain significance in AGAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). Very rare (popmax 0.0039%, nfe).

How common is AGAP2 p.Leu321Val (c.961C>G) in the general population?

AGAP2 p.Leu321Val (c.961C>G) is very rare (popmax 0.0039%, nfe) (gnomAD).

AGAP2 p.Leu321Val

c.961C>G · rs201194295 · VCV2611091

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0039%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.236	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 6,676 bp · p 0.0015 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0039% European (non-Finnish) · 46/1,179,822 alleles

Filtering AF 0.00299% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00267%

Overall 0.00366% 59/1,613,476 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.011%	9,107
Remaining individualsnot grpmax-eligible	0.00961%	10,404
European (non-Finnish)grpmax	0.0039%	25,648

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: AGAP2
Protein: p.Leu321Val
Coding: c.961C>G
MANE Select: NM_001122772
dbSNP: rs201194295
Type: single nucleotide variant
Location: chr12:57737286 (GRCh38)
Gene constraint: LOEUF 0.414 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 60.04 · 3 PDB
Residue 321: the 'interaction with plcg1' region; the 'disordered' region

Full AGAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AGAP2 p.Leu210Gln Uncertain significance ★★ same type
AGAP2 p.Val527= Benign ★★ same type
AGAP2 p.Ala1045Glu Uncertain significance ★ same type
AGAP2 p.Ala1156Thr Uncertain significance ★ same type
AGAP2 p.Ala1161Val Uncertain significance ★ same type
AGAP2 p.Ala116Asp Uncertain significance ★ same type
AGAP2 p.Ala228Val Uncertain significance ★ same type
AGAP2 p.Ala237Thr 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/agap2-p-leu321val (accessed [today's date]).

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