Is AGAP6 p.Ser217Pro (c.649T>C) pathogenic?

AGAP6 p.Ser217Pro (c.649T>C) is classified Uncertain significance in AGAP6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-03). AlphaMissense: likely benign (0.1574); Ultra-rare (popmax 0.028%, afr).

How common is AGAP6 p.Ser217Pro (c.649T>C) in the general population?

AGAP6 p.Ser217Pro (c.649T>C) is ultra-rare (popmax 0.028%, afr) (gnomAD).

What do computational predictors say about AGAP6 p.Ser217Pro (c.649T>C)?

AlphaMissense predicts likely benign (score 0.1574) — an in-silico prediction, not a clinical call.

AGAP6 p.Ser217Pro

c.649T>C · rs1227565433 · VCV2468202

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1574 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.028%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1574	likely benign
REVEL	0.314	indeterminate
SaProt	LLR -10.67	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.4	phastCons 0.037
Regional constraint	o/e 0.64	unconstrained · MANE · 21 kb · p 1.2e-16 · regional, not allelic
Overall
CADD	21.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S194P vs ClinVar S217P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.028% African / African-American · 21/74,888 alleles

Filtering AF 0.0188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0157%

Overall 0.0013% 21/1,613,974 alleles · ultra-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: AGAP6
Protein: p.Ser217Pro
Coding: c.649T>C
MANE Select: NM_001077665
dbSNP: rs1227565433
Type: single nucleotide variant
Location: chr10:50008774 (GRCh38)
Gene constraint: LOEUF 0.757 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 63.73

Full AGAP6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AGAP6 p.Ala105Thr Uncertain significance ★ ⚠ same type
AGAP6 p.Ala109Thr Uncertain significance ★ ⚠ same type
AGAP6 p.Ala135Val Uncertain significance ★ ⚠ same type
AGAP6 p.Ala180Gly Uncertain significance ★ ⚠ same type
AGAP6 p.Ala425Thr Uncertain significance ★ ⚠ same type
AGAP6 p.Ala433Val Uncertain significance ★ ⚠ same type
AGAP6 p.Ala43Ser Uncertain significance ★ ⚠ same type
AGAP6 p.Ala444Pro 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/agap6-p-ser217pro (accessed [today's date]).

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