Is TSC2 p.His76= (c.228C>T) pathogenic?

TSC2 p.His76= (c.228C>T) is classified Benign/Likely benign in TSC2 (ClinVar, Multiple submitters, 22 submitters; last evaluated 2026-06-01). Rare (popmax 0.148%, nfe); Associated with lymphangioleiomyomatosis.

What condition is associated with TSC2 p.His76= (c.228C>T)?

TSC2 p.His76= (c.228C>T) is associated with lymphangioleiomyomatosis, tuberous sclerosis, isolated focal cortical dysplasia type II (ClinVar).

How common is TSC2 p.His76= (c.228C>T) in the general population?

TSC2 p.His76= (c.228C>T) is rare (popmax 0.148%, nfe) (gnomAD).

TSC2 p.His76=

c.228C>T · rs45517097 · VCV49202

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 22 submitters

gnomAD v4.1

Rare

rare (popmax 0.148%, nfe)

Conditions

lymphangioleiomyomatosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.97 · evaluated, not missing
Constraint at this position
Conservation	phyloP -4.8	GERP -3.7
Overall
CADD	6.265	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.148% European (non-Finnish) · 1,719/1,164,342 alleles

Filtering AF 0.142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.139%

Overall 0.203% 3,204/1,580,544 alleles · rare exomes 2,778/1,428,200 · genomes 426/152,344 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.22%	45
Remaining individualsnot grpmax-eligible	0.155%	644
European (non-Finnish)grpmax	0.148%	677
Admixed American	0.0218%	4,598
Middle Eastern	0.0194%	5,148
African / African-American	0.0161%	6,200
Ashkenazi Jewishnot grpmax-eligible	0.0104%	9,657
South Asian	0.00813%	12,300

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.His76=
Coding: c.228C>T
MANE Select: NM_000548
dbSNP: rs45517097
Type: single nucleotide variant
Location: chr16:2053344 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB
Residue 76: an α-helix; the 'required for interaction with tsc1' region

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

Disease context

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

Also linked: tuberous sclerosis isolated focal cortical dysplasia type II tuberous sclerosis 2 hereditary neoplastic syndrome

For Perivascular epithelioid cell neoplasm (Orphanet):

Onset: Adolescent, Adult, Childhood, Elderly

Similar variants

TSC2 p.His76Tyr Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 p.His76Ter 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
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-his76 (accessed [today's date]).

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