Is TSC2 p.His401Pro (c.1202A>C) pathogenic?

TSC2 p.His401Pro (c.1202A>C) is classified Uncertain significance in TSC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-06-23). AlphaMissense: likely benign (0.2983); Absent from gnomAD v4.1; Associated with isolated focal cortical dysplasia type II.

What condition is associated with TSC2 p.His401Pro (c.1202A>C)?

TSC2 p.His401Pro (c.1202A>C) is associated with isolated focal cortical dysplasia type II, tuberous sclerosis 2, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.His401Pro (c.1202A>C) in the general population?

TSC2 p.His401Pro (c.1202A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC2 p.His401Pro (c.1202A>C)?

AlphaMissense predicts likely benign (score 0.2983) — an in-silico prediction, not a clinical call.

TSC2 p.His401Pro

c.1202A>C · rs2086691569 · VCV1301335

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2983 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated focal cortical dysplasia type II

Computational evidence

Protein change
AlphaMissense	0.2983	likely benign
REVEL	0.749	pathogenic-leaning
SaProt	LLR -1.52	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	24.9	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.His401Pro
Coding: c.1202A>C
MANE Select: NM_000548
dbSNP: rs2086691569
Type: single nucleotide variant
Location: chr16:2061953 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB

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

Disease context

isolated focal cortical dysplasia type II — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis 2 hereditary neoplastic syndrome

For Isolated focal cortical dysplasia (Orphanet):

Onset: All ages

Similar variants

TSC2 p.His401Arg Uncertain significance ★★ ⚠ same residue
TSC2 p.His401= Benign/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
TSC2 c.1361+1G>T Pathogenic/Likely pathogenic ★★ same condition
TSC2 c.1362-1G>A Pathogenic ★★ same condition
TSC2 c.138+2T>C 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-his401pro (accessed [today's date]).

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