Is AGAP1 p.Pro326Ala (c.976C>G) pathogenic?

AGAP1 p.Pro326Ala (c.976C>G) is classified Uncertain significance in AGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-05). AlphaMissense: likely benign (0.0566); Ultra-rare (popmax 0.0148%, afr).

How common is AGAP1 p.Pro326Ala (c.976C>G) in the general population?

AGAP1 p.Pro326Ala (c.976C>G) is ultra-rare (popmax 0.0148%, afr) (gnomAD).

What do computational predictors say about AGAP1 p.Pro326Ala (c.976C>G)?

AlphaMissense predicts likely benign (score 0.0566) — an in-silico prediction, not a clinical call.

AGAP1 p.Pro326Ala

c.976C>G · VCV4022475

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0566 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0148%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0566	likely benign
REVEL	0.117	moderately benign-leaning
SaProt	LLR -6.07	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 546 kb · p 0.00065 · regional, not allelic
Overall
CADD	24.5	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 0.0148% African / African-American · 11/74,484 alleles

Filtering AF 0.0082% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00637%

Overall 0.000807% 13/1,610,404 alleles · ultra-rare exomes 7/1,458,256 · genomes 6/152,148 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0148%	6,771
Remaining individualsnot grpmax-eligible	0.00161%	62,296
European (non-Finnish)	8.48e-05%	1,179,090

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: AGAP1
Protein: p.Pro326Ala
Coding: c.976C>G
MANE Select: NM_001037131
Type: single nucleotide variant
Location: chr2:235807257 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.01 · 2 PDB
Residue 326: the 'disordered' region

Full AGAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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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/agap1-p-pro326ala (accessed [today's date]).

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