Is AGAP1 p.Pro102Leu (c.305C>T) pathogenic?

AGAP1 p.Pro102Leu (c.305C>T) is classified Uncertain significance in AGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-15). AlphaMissense: likely pathogenic (0.9574); Very rare (popmax 0.00453%, eas).

How common is AGAP1 p.Pro102Leu (c.305C>T) in the general population?

AGAP1 p.Pro102Leu (c.305C>T) is very rare (popmax 0.00453%, eas) (gnomAD).

What do computational predictors say about AGAP1 p.Pro102Leu (c.305C>T)?

AlphaMissense predicts likely pathogenic (score 0.9574) — an in-silico prediction, not a clinical call.

AGAP1 p.Pro102Leu

c.305C>T · VCV3505246

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9574 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00453%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9574	likely pathogenic
REVEL	0.275	benign-leaning
SaProt	LLR -13.28	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 546 kb · p 0.00065 · regional, not allelic
Overall
CADD	32.0	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 0.00453% East Asian · 2/44,196 alleles

Filtering AF 0.00075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000281%

Overall 0.00075% 12/1,599,962 alleles · very rare exomes 10/1,447,652 · genomes 2/152,310 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00453%	22,098
South Asian	0.00115%	87,248
European (non-Finnish)	0.000765%	130,746

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.Pro102Leu
Coding: c.305C>T
MANE Select: NM_001037131
Type: single nucleotide variant
Location: chr2:235717639 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.01 · 2 PDB
Residue 102: the gld domain; the 'small gtpase-like' region

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

Similar variants

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AGAP1 p.Arg14Trp Uncertain significance ★★ ⚠ same type
AGAP1 p.Arg313His Uncertain significance ★★ ⚠ same type
AGAP1 p.Arg696Trp Uncertain significance ★★ ⚠ same type
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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-pro102leu (accessed [today's date]).

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