Is TSC2 p.Pro665Ala (c.1993C>G) pathogenic?

TSC2 p.Pro665Ala (c.1993C>G) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-13). AlphaMissense: likely benign (0.1335); Ultra-rare (popmax 0.0136%, eas); Associated with tuberous sclerosis.

What condition is associated with TSC2 p.Pro665Ala (c.1993C>G)?

TSC2 p.Pro665Ala (c.1993C>G) is associated with tuberous sclerosis, tuberous sclerosis 2, hereditary neoplastic syndrome (ClinVar).

How common is TSC2 p.Pro665Ala (c.1993C>G) in the general population?

TSC2 p.Pro665Ala (c.1993C>G) is ultra-rare (popmax 0.0136%, eas) (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.Pro665Ala (c.1993C>G)?

AlphaMissense predicts likely benign (score 0.1335) — an in-silico prediction, not a clinical call.

TSC2 p.Pro665Ala

c.1993C>G · rs1184908674 · VCV536057

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1335 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0136%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

tuberous sclerosis

Computational evidence

Protein change
AlphaMissense	0.1335	likely benign
REVEL	0.467	indeterminate
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 1.1, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	21.2	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 0.0136% East Asian · 6/44,050 alleles

Filtering AF 0.00588% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.004%

Overall 0.000376% 6/1,596,926 alleles · ultra-rare exomes 4/1,444,820 · genomes 2/152,106 · 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.Pro665Ala
Coding: c.1993C>G
MANE Select: NM_000548
dbSNP: rs1184908674
Type: single nucleotide variant
Location: chr16:2071830 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 665: the 'disordered' region

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

Disease context

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

Also linked: tuberous sclerosis 2 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.Pro665Leu Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro665Ser 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
TSC2 c.138+2T>C 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-pro665ala (accessed [today's date]).

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