Is TP53 p.Leu206Ser (c.617T>C) pathogenic?

TP53 p.Leu206Ser (c.617T>C) is classified Conflicting classifications of pathogenicity in TP53 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-03-20). AlphaMissense: likely benign (0.1231); Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 p.Leu206Ser (c.617T>C)?

TP53 p.Leu206Ser (c.617T>C) is associated with hereditary neoplastic syndrome, Li-Fraumeni syndrome (ClinVar).

How common is TP53 p.Leu206Ser (c.617T>C) in the general population?

TP53 p.Leu206Ser (c.617T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TP53 p.Leu206Ser (c.617T>C)?

AlphaMissense predicts likely benign (score 0.1231) — an in-silico prediction, not a clinical call.

TP53 p.Leu206Ser

c.617T>C · rs1555525804 · VCV439319

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1231 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.1231	likely benign
REVEL	0.605	indeterminate
SaProt	LLR -9.25	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3	GERP 1.3, phastCons 0.22
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	17.16	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 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.2e-05% 1/1,614,186 alleles · very rare exomes 1/1,461,890 · genomes 0/152,296 · 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
Protein: p.Leu206Ser
Coding: c.617T>C
MANE Select: NM_000546
dbSNP: rs1555525804
Type: single nucleotide variant
Location: chr17:7674914 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 206: a DNA-binding region; the 'interaction with axin1' region; a β-strand; the 'interaction with ccar2' region; the 'interaction with hipk1' region; a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); the 'required for interaction with znf385a' region; the 'required for interaction with fbxo42' region

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

Also linked: Li-Fraumeni syndrome

Similar variants

TP53 p.Leu206= Benign/Likely benign ★★ same residue
TP53 p.Leu206Phe Uncertain significance ★ ⚠ same residue
TP53 p.Leu206Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Leu206fs Pathogenic ★ same residue
TP53 p.Leu206Ter Pathogenic ★ same residue
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

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-p-leu206ser (accessed [today's date]).

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