Is TSC1 p.Ser671Arg (c.2013C>A) pathogenic?

TSC1 p.Ser671Arg (c.2013C>A) is classified Uncertain significance in TSC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-08-07). AlphaMissense: likely pathogenic (0.9234); Very rare (popmax 8.47e-05%, nfe); Associated with tuberous sclerosis 1.

What condition is associated with TSC1 p.Ser671Arg (c.2013C>A)?

TSC1 p.Ser671Arg (c.2013C>A) is associated with tuberous sclerosis 1 (ClinVar).

How common is TSC1 p.Ser671Arg (c.2013C>A) in the general population?

TSC1 p.Ser671Arg (c.2013C>A) is very rare (popmax 8.47e-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 TSC1 p.Ser671Arg (c.2013C>A)?

AlphaMissense predicts likely pathogenic (score 0.9234) — an in-silico prediction, not a clinical call.

TSC1 p.Ser671Arg

c.2013C>A · rs1845545985 · VCV1010024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tuberous sclerosis 1

Computational evidence

Protein change
AlphaMissense	0.9234	likely pathogenic · top 8% in TSC1
REVEL	0.678	pathogenic-leaning
SaProt	LLR -7.11	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 4,448 bp · p 0.00013 · regional, not allelic
Overall
CADD	26.7	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

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 6.84e-05% 1/1,461,708 alleles · very rare

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: TSC1
Protein: p.Ser671Arg
Coding: c.2013C>A
MANE Select: NM_000368
dbSNP: rs1845545985
Type: single nucleotide variant
Location: chr9:132904439 (GRCh38)
Gene constraint: LOEUF 0.227 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 63.55 · 5 PDB
Residue 671: the 'mediates interaction with wdr45b' region; an α-helix; a UniProt-annotated variant site (in tsc1)

Full TSC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tuberous sclerosis 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Tuberous sclerosis complex (Orphanet):

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

Similar variants

TSC1 p.Ser671Asn Uncertain significance ★★ same residue
TSC1 p.Ser671Ile Uncertain significance ★★ ⚠ same residue
TSC1 p.Ser671Thr Uncertain significance ★★ ⚠ same residue
TSC1 p.Ser671= Conflicting classifications of pathogenicity ★ same residue
TSC1 p.Ser671Gly Likely benign ★ ⚠ same residue
TSC1 p.Ser671fs Pathogenic ★ same residue
TSC1 c.1029+1G>A Pathogenic/Likely pathogenic ★★ same condition
TSC1 c.1029+1G>C 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-ser671arg (accessed [today's date]).

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