Is TFAP2B p.Pro259Ser (c.775C>T) pathogenic?

TFAP2B p.Pro259Ser (c.775C>T) is classified Uncertain significance in TFAP2B (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-30). AlphaMissense: likely pathogenic (0.9448); Ultra-rare (popmax 0.015%, amr); Associated with Inborn genetic diseases.

What condition is associated with TFAP2B p.Pro259Ser (c.775C>T)?

TFAP2B p.Pro259Ser (c.775C>T) is associated with Inborn genetic diseases (ClinVar).

How common is TFAP2B p.Pro259Ser (c.775C>T) in the general population?

TFAP2B p.Pro259Ser (c.775C>T) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about TFAP2B p.Pro259Ser (c.775C>T)?

AlphaMissense predicts likely pathogenic (score 0.9448) — an in-silico prediction, not a clinical call.

TFAP2B p.Pro259Ser

c.775C>T · VCV3325590

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9448 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9448	likely pathogenic
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -10.13	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.41	unconstrained · MANE · 4,023 bp · p 1.1e-09 · regional, not allelic
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.015% Admixed American · 9/60,004 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00578%

Overall 0.000682% 11/1,612,732 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,667
Remaining individualsnot grpmax-eligible	0.00321%	31,184

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: TFAP2B
Protein: p.Pro259Ser
Coding: c.775C>T
MANE Select: NM_003221
Type: single nucleotide variant
Location: chr6:50836234 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.95 · 1 PDB
Residue 259: a turn

Full TFAP2B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TFAP2B p.Ala54Gly Uncertain significance ★★ same condition
TFAP2B p.Asp346Glu Uncertain significance ★★ same condition
TFAP2B p.Pro205Ser Uncertain significance ★★ ⚠ same condition
TFAP2B c.601+1G>A Pathogenic ★ same condition
TFAP2B p.Tyr51Ter Pathogenic ★ same condition
TFAP2B p.Ala333Thr Uncertain significance ★ ⚠ same condition
TFAP2B p.Arg29Leu Uncertain significance ★ ⚠ same condition
TFAP2B p.Arg342Gln Uncertain significance ★ ⚠ 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/tfap2b-p-pro259ser (accessed [today's date]).

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