Is AGAP5 p.Leu643Pro (c.1928T>C) pathogenic?

AGAP5 p.Leu643Pro (c.1928T>C) is classified Uncertain significance in AGAP5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely pathogenic (0.6997); Very rare (popmax 0.0011%, sas).

How common is AGAP5 p.Leu643Pro (c.1928T>C) in the general population?

AGAP5 p.Leu643Pro (c.1928T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about AGAP5 p.Leu643Pro (c.1928T>C)?

AlphaMissense predicts likely pathogenic (score 0.6997) — an in-silico prediction, not a clinical call.

AGAP5 p.Leu643Pro

c.1928T>C · VCV4638860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6997 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6997	likely pathogenic · top 2% in AGAP5
REVEL	0.506	indeterminate
SaProt	LLR -12.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3	GERP 0.7, phastCons 0.99
Regional constraint	o/e 0.57	unconstrained · MANE · 112 bp · p 0.0017 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/90,992 alleles

Overall 6.85e-05% 1/1,459,800 alleles · very rare

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: AGAP5
Protein: p.Leu643Pro
Coding: c.1928T>C
MANE Select: NM_001144000
Type: single nucleotide variant
Location: chr10:73674732 (GRCh38)
Gene constraint: LOEUF 0.717 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 62.80

Full AGAP5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AGAP5 p.Ala195Val Uncertain significance ★ ⚠ same type
AGAP5 p.Ala397Thr Uncertain significance ★ ⚠ same type
AGAP5 p.Ala41Glu Uncertain significance ★ ⚠ same type
AGAP5 p.Ala43Val Uncertain significance ★ ⚠ same type
AGAP5 p.Ala444Thr Uncertain significance ★ ⚠ same type
AGAP5 p.Ala596Thr Uncertain significance ★ ⚠ same type
AGAP5 p.Ala608Thr Uncertain significance ★ ⚠ same type
AGAP5 p.Ala608Val 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/agap5-p-leu643pro (accessed [today's date]).

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