Is TFAP2B p.Val253Phe (c.757G>T) pathogenic?

TFAP2B p.Val253Phe (c.757G>T) is classified Uncertain significance in TFAP2B (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-20). AlphaMissense: likely pathogenic (0.999); Absent from gnomAD v4.1.

How common is TFAP2B p.Val253Phe (c.757G>T) in the general population?

TFAP2B p.Val253Phe (c.757G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TFAP2B p.Val253Phe (c.757G>T)?

AlphaMissense predicts likely pathogenic (score 0.999) — an in-silico prediction, not a clinical call.

TFAP2B p.Val253Phe

c.757G>T · rs2533143515 · VCV2580390

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.999 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.999	likely pathogenic
REVEL	0.934	strongly pathogenic-leaning
SaProt	LLR -13.99	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 12	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	27.3	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TFAP2B
Protein: p.Val253Phe
Coding: c.757G>T
MANE Select: NM_003221
dbSNP: rs2533143515
Type: single nucleotide variant
Location: chr6:50836216 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.95 · 1 PDB
Residue 253: an α-helix

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

Similar variants

TFAP2B p.Arg236His Likely pathogenic ★★ same type
TFAP2B p.Arg285Gln Pathogenic/Likely pathogenic ★★ same type
TFAP2B p.Ala54Gly Uncertain significance ★★ same type
TFAP2B p.Asp31Gly Uncertain significance ★★ ⚠ same type
TFAP2B p.Asp346Glu Uncertain significance ★★ same type
TFAP2B p.Pro205Ser Uncertain significance ★★ ⚠ same type
TFAP2B p.Ser277Trp Uncertain significance ★★ ⚠ same type
TFAP2B p.Thr306Met Uncertain significance ★★ ⚠ 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/tfap2b-p-val253phe (accessed [today's date]).

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