Is TP53 c.993+3A>T pathogenic?

TP53 c.993+3A>T is classified Uncertain significance in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-06-17). Very rare (popmax 0.0011%, sas); Associated with Li-Fraumeni syndrome.

What condition is associated with TP53 c.993+3A>T?

TP53 c.993+3A>T is associated with Li-Fraumeni syndrome (ClinVar).

How common is TP53 c.993+3A>T in the general population?

TP53 c.993+3A>T is very rare (popmax 0.0011%, sas) (gnomAD).

How is Li-Fraumeni syndrome inherited?

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

TP53 c.993+3A>T

rs2151010771 · VCV1499603

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Li-Fraumeni syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +3	donor splice region (+3, within the first 6 intronic nt) · inside the BP7-excluded zone
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.73	loss · gain 0.01 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 5.1	GERP 2.1, phastCons 1
Overall
CADD	19.33	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,086 alleles

Overall 6.2e-05% 1/1,613,844 alleles · very rare exomes 1/1,461,556 · genomes 0/152,288 · 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: TP53
Coding: c.993+3A>T
MANE Select: NM_000546
dbSNP: rs2151010771
Type: single nucleotide variant
Location: chr17:7673532 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB

Full TP53 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Li-Fraumeni syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Li-Fraumeni syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: All ages
Prevalence: 1-9 / 100 000 (United Kingdom)

Similar variants

TP53 c.375+5G>A Likely pathogenic ★★★ same condition
TP53 c.919+1G>A Pathogenic ★★★ same condition
TP53 c.97-1G>A Pathogenic ★★★ same condition
TP53 p.Ala138Pro Likely pathogenic ★★★ same condition
TP53 p.Ala138Val Likely pathogenic ★★★ same condition
TP53 p.Ala347Asp Pathogenic ★★★ same condition
TP53 p.Arg110Gly Likely pathogenic ★★★ ⚠ same condition
TP53 p.Arg110Leu 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/tp53-c-993-plus-3a-t (accessed [today's date]).

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