Is AGAP1 p.Pro520Ala (c.1558C>G) pathogenic?

AGAP1 p.Pro520Ala (c.1558C>G) is classified Uncertain significance in AGAP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-24). AlphaMissense: likely benign (0.1147); Rare (popmax 0.321%, mid).

How common is AGAP1 p.Pro520Ala (c.1558C>G) in the general population?

AGAP1 p.Pro520Ala (c.1558C>G) is rare (popmax 0.321%, mid) (gnomAD).

What do computational predictors say about AGAP1 p.Pro520Ala (c.1558C>G)?

AlphaMissense predicts likely benign (score 0.1147) — an in-silico prediction, not a clinical call.

AGAP1 p.Pro520Ala

c.1558C>G · rs368285811 · VCV2171999

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1147 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.321%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1147	likely benign
REVEL	0.263	benign-leaning
SaProt	LLR -10.79	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 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 546 kb · p 0.00065 · regional, not allelic
Overall
CADD	24.7	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 0.321% Middle Eastern · 12/3,734 alleles

Filtering AF 0.185% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.145%

Overall 0.00725% 56/772,220 alleles · rare exomes 52/644,506 · genomes 4/127,714 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.321%	311
Ashkenazi Jewishnot grpmax-eligible	0.0527%	1,898
Remaining individualsnot grpmax-eligible	0.0143%	6,970
South Asian	0.011%	9,074
East Asian	0.00538%	18,594
European (non-Finnish)	0.00424%	23,605
Finnishnot grpmax-eligible	0.00233%	42,946

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.Pro520Ala
Coding: c.1558C>G
MANE Select: NM_001037131
dbSNP: rs368285811
Type: single nucleotide variant
Location: chr2:235968536 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.01 · 2 PDB
Residue 520: the 'disordered' region; the ph domain

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

Similar variants

AGAP1 p.Pro520Arg Uncertain significance ★★ ⚠ same residue
AGAP1 p.Ala418Ser Uncertain significance ★★ ⚠ same type
AGAP1 p.Ala52Ser Uncertain significance ★★ ⚠ same type
AGAP1 p.Ala570Gly Uncertain significance ★★ same type
AGAP1 p.Ala809Ser Uncertain significance ★★ ⚠ same type
AGAP1 p.Arg14Trp Uncertain significance ★★ ⚠ same type
AGAP1 p.Arg313His Uncertain significance ★★ ⚠ same type
AGAP1 p.Arg696Trp 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/agap1-p-pro520ala (accessed [today's date]).

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