Is TP53BP1 p.Ser285Phe (c.854C>T) pathogenic?

TP53BP1 p.Ser285Phe (c.854C>T) is classified Uncertain significance in TP53BP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-19). AlphaMissense: likely benign (0.1193); Very rare (popmax 0.0022%, sas).

How common is TP53BP1 p.Ser285Phe (c.854C>T) in the general population?

TP53BP1 p.Ser285Phe (c.854C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about TP53BP1 p.Ser285Phe (c.854C>T)?

AlphaMissense predicts likely benign (score 0.1193) — an in-silico prediction, not a clinical call.

TP53BP1 p.Ser285Phe

c.854C>T · VCV3972476

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1193 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1193	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -8.89	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP -0.062, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 72 kb · p 0.8 · regional, not allelic
Overall
CADD	18.47	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S280F vs ClinVar S285F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/91,006 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,613,632 alleles · very rare exomes 3/1,461,304 · genomes 0/152,328 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,503
European (non-Finnish)	8.48e-05%	1,179,823

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: TP53BP1
Protein: p.Ser285Phe
Coding: c.854C>T
MANE Select: NM_001141980
Type: single nucleotide variant
Location: chr15:43477694 (GRCh38)
Gene constraint: LOEUF 0.364 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 44.67 · 45 PDB

Full TP53BP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TUBGCP4 p.Leu582= Pathogenic/Likely pathogenic ★★ same type
TP53BP1 p.Gln1009Arg Uncertain significance ★★ ⚠ same type
TUBGCP4 p.Arg633Gln Uncertain significance ★★ ⚠ same type
TUBGCP4 p.Asp587Ala Uncertain significance ★★ ⚠ same type
TP53BP1 p.Ala750= Benign/Likely benign ★★ same type
TP53BP1 p.Cys1830= Likely benign ★★ same type
TP53BP1 p.Ser299Pro Benign/Likely benign ★★ same type
TP53BP1 p.Thr553Ala Benign ★★ same type

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/tp53bp1-p-ser285phe (accessed [today's date]).

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