Is TP63 p.Ile96Val (c.286A>G) pathogenic?

TP63 p.Ile96Val (c.286A>G) is classified Uncertain significance in TP63 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-27). AlphaMissense: likely benign (0.1047); Very rare (popmax 0.000339%, nfe); Associated with TP63-Related Spectrum Disorders.

What condition is associated with TP63 p.Ile96Val (c.286A>G)?

TP63 p.Ile96Val (c.286A>G) is associated with TP63-Related Spectrum Disorders (ClinVar).

How common is TP63 p.Ile96Val (c.286A>G) in the general population?

TP63 p.Ile96Val (c.286A>G) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about TP63 p.Ile96Val (c.286A>G)?

AlphaMissense predicts likely benign (score 0.1047) — an in-silico prediction, not a clinical call.

TP63 p.Ile96Val

c.286A>G · rs372543100 · VCV1436296

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1047 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TP63-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.1047	likely benign
REVEL	0.489	indeterminate
SaProt	LLR -1.57	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.1	GERP 2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 177 kb · p 0.031 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,180,016 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,022 alleles · very rare exomes 3/1,461,828 · genomes 1/152,194 · 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: TP63
Protein: p.Ile96Val
Coding: c.286A>G
MANE Select: NM_003722
dbSNP: rs372543100
Type: single nucleotide variant
Location: chr3:189738736 (GRCh38)
Gene constraint: LOEUF 0.296 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 63.70 · 26 PDB
Residue 96: the 'transcription activation' region

Full TP63 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

TP63-Related Spectrum Disorders

Similar variants

TP63 p.Arg318His Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Cys561Tyr Likely pathogenic ★★ same condition
TP63 p.Gly173Arg Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Gly173Asp Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Gly336Asp Pathogenic/Likely pathogenic ★★ same condition
TP63 p.Gly557Val Pathogenic/Likely pathogenic ★★ same condition
TP63 p.His247Arg Pathogenic ★★ same condition
TP63 p.His247Tyr Pathogenic/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/tp63-p-ile96val (accessed [today's date]).

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