Is TSC2 p.Pro1737Ser (c.5209C>T) pathogenic?

TSC2 p.Pro1737Ser (c.5209C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.526); Ultra-rare (popmax 0.0232%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro1737Ser (c.5209C>T)?

TSC2 p.Pro1737Ser (c.5209C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro1737Ser (c.5209C>T) in the general population?

TSC2 p.Pro1737Ser (c.5209C>T) is ultra-rare (popmax 0.0232%, sas) (gnomAD).

What do computational predictors say about TSC2 p.Pro1737Ser (c.5209C>T)?

AlphaMissense predicts ambiguous (score 0.526) — an in-silico prediction, not a clinical call.

TSC2 p.Pro1737Ser

c.5209C>T · rs780112037 · VCV238078

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

ambiguous

0.526 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0232%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.526	ambiguous
REVEL	0.692	pathogenic-leaning
SaProt	LLR -4.81	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	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	25.8	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 0.0232% South Asian · 21/90,616 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.013%

Overall 0.00306% 49/1,602,068 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0232%	4,315
Middle Eastern	0.0165%	6,068
Admixed American	0.0101%	9,853
East Asian	0.00675%	14,817
Remaining individualsnot grpmax-eligible	0.00642%	15,576
European (non-Finnish)	0.00119%	83,955

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.Pro1737Ser
Coding: c.5209C>T
MANE Select: NM_000548
dbSNP: rs780112037
Type: single nucleotide variant
Location: chr16:2088275 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1737: the rap-gap domain

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.Pro1737= Benign/Likely benign ★★ same residue
TSC2 p.Pro1737Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1737Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.Pro1737Thr Uncertain significance ★ ⚠ same residue
TSC2 p.Pro1737fs Pathogenic ★ 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-pro1737ser (accessed [today's date]).

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