Is TSC2 p.Ala1722Pro (c.5164G>C) pathogenic?

TSC2 p.Ala1722Pro (c.5164G>C) is classified Likely pathogenic in TSC2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-17). AlphaMissense: likely pathogenic (0.9967); Absent from gnomAD v4.1; Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Ala1722Pro (c.5164G>C)?

TSC2 p.Ala1722Pro (c.5164G>C) is associated with tuberous sclerosis 2, tuberous sclerosis (ClinVar).

How common is TSC2 p.Ala1722Pro (c.5164G>C) in the general population?

TSC2 p.Ala1722Pro (c.5164G>C) is absent from gnomAD v4.1 (gnomAD).

How is Tuberous sclerosis complex inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TSC2 p.Ala1722Pro (c.5164G>C)?

AlphaMissense predicts likely pathogenic (score 0.9967) — an in-silico prediction, not a clinical call.

TSC2 p.Ala1722Pro

c.5164G>C · rs397515270 · VCV65360

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9967 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.9967	likely pathogenic ✓ concordant with ClinVar · top 2% in TSC2
REVEL	0.892	moderately pathogenic-leaning
SaProt	LLR -15.44	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.25 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.6, phastCons 1
Regional constraint	o/e 1.27	unconstrained · MANE · 1,785 bp · p 3.9e-05 · regional, not allelic
Overall
CADD	28.2	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TSC2
Protein: p.Ala1722Pro
Coding: c.5164G>C
MANE Select: NM_000548
dbSNP: rs397515270
Type: single nucleotide variant
Location: chr16:2088230 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1722: the rap-gap domain; an α-helix

Full TSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tuberous sclerosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis

For Tuberous sclerosis complex (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Taiwan, Province of China)

Similar variants

TSC2 p.Ala1722Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Ala1722Asp Likely pathogenic ★ same residue
TSC2 p.Ala1722Ser Uncertain significance ★ ⚠ same residue
TSC2 p.Ala1722Val Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Ala1722= Likely benign ★ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G Pathogenic ★★ same condition
TSC2 c.1361+1G>A Pathogenic/Likely pathogenic ★★ same condition

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/tsc2-p-ala1722pro (accessed [today's date]).

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