Is TSC2 p.Pro1441Ser (c.4321C>T) pathogenic?

TSC2 p.Pro1441Ser (c.4321C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.0726); Very rare (popmax 8.48e-05%, nfe); Associated with tuberous sclerosis 2.

What condition is associated with TSC2 p.Pro1441Ser (c.4321C>T)?

TSC2 p.Pro1441Ser (c.4321C>T) is associated with tuberous sclerosis 2, tuberous sclerosis, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Pro1441Ser (c.4321C>T) in the general population?

TSC2 p.Pro1441Ser (c.4321C>T) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Tuberous sclerosis complex inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TSC2 p.Pro1441Ser (c.4321C>T)?

AlphaMissense predicts likely benign (score 0.0726) — an in-silico prediction, not a clinical call.

TSC2 p.Pro1441Ser

c.4321C>T · rs201710642 · VCV388436

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

tuberous sclerosis 2

Computational evidence

Protein change
AlphaMissense	0.0726	likely benign
REVEL	0.488	indeterminate
SaProt	LLR -6.23	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.17	GERP -0.57
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	12.77	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 8.48e-05% European (non-Finnish) · 1/1,179,314 alleles

Overall 0.000124% 2/1,608,952 alleles · very rare exomes 2/1,456,590 · genomes 0/152,362 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00166%	60,224
European (non-Finnish)grpmax	8.48e-05%	1,179,313

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro1441Ser
Coding: c.4321C>T
MANE Select: NM_000548
dbSNP: rs201710642
Type: single nucleotide variant
Location: chr16:2084543 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 1441: the 'disordered' region

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

Disease context

tuberous sclerosis 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tuberous sclerosis hereditary neoplastic syndrome

For Tuberous sclerosis complex (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (Taiwan, Province of China)

Similar variants

TSC2 p.Pro1441= Benign/Likely benign ★★ same residue
TSC2 p.Pro1441Arg Uncertain significance ★ ⚠ same residue
TSC2 p.Pro1441Leu 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
TSC2 c.1362-1G>A 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-pro1441ser (accessed [today's date]).

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