Is TSC2 p.Ser735Pro (c.2203T>C) pathogenic?

TSC2 p.Ser735Pro (c.2203T>C) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-12-14). AlphaMissense: likely pathogenic (0.7218); Very rare (popmax 6.2e-05%); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Ser735Pro (c.2203T>C)?

TSC2 p.Ser735Pro (c.2203T>C) is associated with hereditary neoplastic syndrome, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Ser735Pro (c.2203T>C) in the general population?

TSC2 p.Ser735Pro (c.2203T>C) is very rare (popmax 6.2e-05%) (gnomAD).

What do computational predictors say about TSC2 p.Ser735Pro (c.2203T>C)?

AlphaMissense predicts likely pathogenic (score 0.7218) — an in-silico prediction, not a clinical call.

TSC2 p.Ser735Pro

c.2203T>C · rs753059579 · VCV1367368

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7218 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.7218	likely pathogenic
REVEL	0.669	pathogenic-leaning
SaProt	LLR -12.03	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP 1.1, phastCons 0.99
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	21.6	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 6.2e-05%

Overall 6.2e-05% 1/1,614,122 alleles · very rare exomes 1/1,461,772 · genomes 0/152,350 · joint denominator

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: TSC2
Protein: p.Ser735Pro
Coding: c.2203T>C
MANE Select: NM_000548
dbSNP: rs753059579
Type: single nucleotide variant
Location: chr16:2072346 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 735: an α-helix

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis 2

Similar variants

TSC2 p.Ser735= Likely benign ★★ same residue
TSC2 p.Ser735Cys Uncertain significance ★ ⚠ same residue
TSC2 p.Ser735Phe Uncertain significance ★ ⚠ same residue
TSC2 p.Ser735Ala Uncertain significance ★ ⚠ 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

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-ser735pro (accessed [today's date]).

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