Is TP53 c.993+331A>G pathogenic?

TP53 c.993+331A>G is classified Likely benign in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-30). Very rare (popmax 0.00399%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 c.993+331A>G?

TP53 c.993+331A>G is associated with hereditary neoplastic syndrome (ClinVar).

How common is TP53 c.993+331A>G in the general population?

TP53 c.993+331A>G is very rare (popmax 0.00399%, amr) (gnomAD).

TP53 c.993+331A>G

rs1438885967 · VCV628372

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00399%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +331	deep intronic (+331 nt into the intron)
SpliceAI	<0.2	all four deltas below 0.2 · T>A here scores Δ0.28 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.61	GERP 0.32, phastCons 0.002
Overall
CADD	12.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00399% Admixed American · 2/50,144 alleles

Filtering AF 0.000661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000247%

Overall 0.000207% 2/967,726 alleles · very rare exomes 1/816,278 · genomes 1/151,448 · 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+331A>G
MANE Select: NM_000546
dbSNP: rs1438885967
Type: single nucleotide variant
Location: chr17:7673204 (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

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-331a-g (accessed [today's date]).

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