Is TSC1 p.Pro358Ser (c.1072C>T) pathogenic?

TSC1 p.Pro358Ser (c.1072C>T) is classified Uncertain significance in TSC1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-17). AlphaMissense: likely pathogenic (0.7949); Absent from gnomAD v4.1; Associated with isolated focal cortical dysplasia type II.

What condition is associated with TSC1 p.Pro358Ser (c.1072C>T)?

TSC1 p.Pro358Ser (c.1072C>T) is associated with isolated focal cortical dysplasia type II, tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Pro358Ser (c.1072C>T) in the general population?

TSC1 p.Pro358Ser (c.1072C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TSC1 p.Pro358Ser (c.1072C>T)?

AlphaMissense predicts likely pathogenic (score 0.7949) — an in-silico prediction, not a clinical call.

TSC1 p.Pro358Ser

c.1072C>T · rs1845931311 · VCV2897677

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7949 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated focal cortical dysplasia type II

Computational evidence

Protein change
AlphaMissense	0.7949	likely pathogenic
REVEL	0.746	pathogenic-leaning
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.76	unconstrained · MANE · 23 kb · p 5.3e-09 · regional, not allelic
Overall
CADD	27.7	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: TSC1
Protein: p.Pro358Ser
Coding: c.1072C>T
MANE Select: NM_000368
dbSNP: rs1845931311
Type: single nucleotide variant
Location: chr9:132911071 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 358: a UniProt-annotated variant site (in tsc1)

Full TSC1 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 1

For Isolated focal cortical dysplasia (Orphanet):

Onset: All ages

Similar variants

TSC1 p.Pro358Leu Uncertain significance ★★ ⚠ same residue
TSC1 p.Pro358fs Pathogenic ★ same residue
TSC1 p.Pro358Thr Uncertain significance ★ ⚠ same residue
TSC1 c.1029+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1029+1G>C Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.107-1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1141+1G>A Likely pathogenic ★★ same condition
TSC1 c.1264-1G>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/tsc1-p-pro358ser (accessed [today's date]).

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