Is TP53 p.Met66Val (c.196A>G) pathogenic?

TP53 p.Met66Val (c.196A>G) is classified Likely benign in TP53 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-15). AlphaMissense: likely benign (0.0722); Very rare (popmax 0.0011%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with TP53 p.Met66Val (c.196A>G)?

TP53 p.Met66Val (c.196A>G) is associated with hereditary neoplastic syndrome (ClinVar).

How common is TP53 p.Met66Val (c.196A>G) in the general population?

TP53 p.Met66Val (c.196A>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about TP53 p.Met66Val (c.196A>G)?

AlphaMissense predicts likely benign (score 0.0722) — an in-silico prediction, not a clinical call.

TP53 p.Met66Val

c.196A>G · rs2073477248 · VCV1783578

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0722	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -4.10	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.9	GERP -4.1
Regional constraint	o/e 0.89	unconstrained · MANE · 6,982 bp · p 0.0085 · regional, not allelic
Overall
CADD	0.012	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 0.0011% South Asian · 1/91,066 alleles

Overall 6.2e-05% 1/1,613,876 alleles · very rare exomes 0/1,461,800 · genomes 1/152,076 · 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.Met66Val
Coding: c.196A>G
MANE Select: NM_000546
dbSNP: rs2073477248
Type: single nucleotide variant
Location: chr17:7676173 (GRCh38)
Gene constraint: LOEUF 0.449 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 75.83 · 321 PDB
Residue 66: a UniProt-annotated variant site (in a sporadic cancer; somatic mutation); the 'interaction with ccar2' region; the 'interaction with hrmt1l2' region; the 'disordered' region; the 'interaction with wwox' 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

Similar variants

TP53 p.Met66Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
TP53 p.Met66Arg Uncertain significance ★★ ⚠ same residue
TP53 p.Met66Thr Uncertain significance ★ ⚠ 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
TP53 p.Ala138Pro Likely pathogenic ★★★ same condition
TP53 p.Ala138Val Likely 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-met66val (accessed [today's date]).

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