Is TSC2 p.Pro542Ser (c.1624C>T) pathogenic?

TSC2 p.Pro542Ser (c.1624C>T) is classified Conflicting classifications of pathogenicity in TSC2 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-12-09). AlphaMissense: likely benign (0.0981); Very rare (popmax 0.00267%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with TSC2 p.Pro542Ser (c.1624C>T)?

TSC2 p.Pro542Ser (c.1624C>T) is associated with hereditary neoplastic syndrome, tuberous sclerosis, tuberous sclerosis 2 (ClinVar).

How common is TSC2 p.Pro542Ser (c.1624C>T) in the general population?

TSC2 p.Pro542Ser (c.1624C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TSC2 p.Pro542Ser (c.1624C>T)?

AlphaMissense predicts likely benign (score 0.0981) — an in-silico prediction, not a clinical call.

TSC2 p.Pro542Ser

c.1624C>T · rs891347695 · VCV1000572

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0981	likely benign
REVEL	0.216	benign-leaning
SaProt	LLR -4.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>G here scores Δ0.88 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.2	GERP 0.97, phastCons 1
Regional constraint	o/e 1.00	unconstrained · MANE · 37 kb · p 0.88 · regional, not allelic
Overall
CADD	19.92	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 0.00267% African / African-American · 2/74,910 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.00093% 15/1,613,616 alleles · very rare exomes 14/1,461,456 · genomes 1/152,160 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,455
European (non-Finnish)	0.0011%	90,766

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.Pro542Ser
Coding: c.1624C>T
MANE Select: NM_000548
dbSNP: rs891347695
Type: single nucleotide variant
Location: chr16:2065543 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 68.81 · 2 PDB

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.Pro542His Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro542Thr Uncertain significance ★★ ⚠ same residue
TSC2 p.Pro542= Benign/Likely benign ★★ same residue
TSC2 p.Pro542Ala Uncertain significance ★ ⚠ same residue
TSC2 p.Pro542Arg Uncertain significance ★ ⚠ same residue
TSC2 p.Pro542Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
TSC2 c.1257+1G>A Pathogenic ★★ same condition
TSC2 c.1258-2A>G 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-pro542ser (accessed [today's date]).

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