Is AGAP1 p.Ser490Leu (c.1469C>T) pathogenic?

AGAP1 p.Ser490Leu (c.1469C>T) is classified Uncertain significance in AGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-20). AlphaMissense: likely benign (0.16); Very rare (popmax 0.00892%, eas).

How common is AGAP1 p.Ser490Leu (c.1469C>T) in the general population?

AGAP1 p.Ser490Leu (c.1469C>T) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about AGAP1 p.Ser490Leu (c.1469C>T)?

AlphaMissense predicts likely benign (score 0.16) — an in-silico prediction, not a clinical call.

AGAP1 p.Ser490Leu

c.1469C>T · VCV3505206

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.16 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.16	likely benign
REVEL	0.337	indeterminate
SaProt	LLR -11.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.20 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.8	GERP 0.38, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 546 kb · p 0.00065 · regional, not allelic
Overall
CADD	28.3	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 0.00892% East Asian · 4/44,822 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00105% 17/1,613,786 alleles · very rare exomes 13/1,461,492 · genomes 4/152,294 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,205
Remaining individualsnot grpmax-eligible	0.0064%	15,619
African / African-American	0.004%	25,010
Admixed American	0.00167%	59,990
European (non-Finnish)	0.000424%	235,976

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.Ser490Leu
Coding: c.1469C>T
MANE Select: NM_001037131
Type: single nucleotide variant
Location: chr2:235930909 (GRCh38)
Gene constraint: LOEUF 0.366 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 72.01 · 2 PDB
Residue 490: the ph domain

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-ser490leu (accessed [today's date]).

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