Is TSC2 p.Arg786His (c.2357G>A) pathogenic?

TSC2 p.Arg786His (c.2357G>A) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-02-11). AlphaMissense: likely benign (0.3007); Very rare (popmax 0.0028%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Arg786His (c.2357G>A)?

TSC2 p.Arg786His (c.2357G>A) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Arg786His (c.2357G>A) in the general population?

TSC2 p.Arg786His (c.2357G>A) is very rare (popmax 0.0028%, nfe) (gnomAD).

What do computational predictors say about TSC2 p.Arg786His (c.2357G>A)?

AlphaMissense predicts likely benign (score 0.3007) — an in-silico prediction, not a clinical call.

TSC2 p.Arg786His

c.2357G>A · rs796053511 · VCV207782

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.3007 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.3007	likely benign
REVEL	0.745	pathogenic-leaning
SaProt	LLR -7.01	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 12	GERP 2.3, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	33.0	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 0.0028% European (non-Finnish) · 33/1,179,906 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00211% 34/1,610,980 alleles · very rare exomes 33/1,458,742 · genomes 1/152,238 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,755
Admixed American	0.00167%	59,994

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.Arg786His
Coding: c.2357G>A
MANE Select: NM_000548
dbSNP: rs796053511
Type: single nucleotide variant
Location: chr16:2074201 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 786: 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 tuberous sclerosis 2

Similar variants

TSC2 p.Arg786Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Arg786Ser Uncertain significance ★★ ⚠ same residue
TSC2 p.Arg786= Conflicting classifications of pathogenicity ★ same residue
TSC2 p.Arg786Cys Conflicting classifications of pathogenicity ★ ⚠ 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-arg786his (accessed [today's date]).

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