Is TFAP2B p.Pro73Arg (c.218C>G) pathogenic?

TFAP2B p.Pro73Arg (c.218C>G) is classified Pathogenic in TFAP2B (ClinVar, No assertion criteria, 2 submitters; last evaluated 2001-10-01). AlphaMissense: likely pathogenic (0.9882); Very rare (popmax 8.47e-05%, nfe); Associated with Char syndrome.

What condition is associated with TFAP2B p.Pro73Arg (c.218C>G)?

TFAP2B p.Pro73Arg (c.218C>G) is associated with Char syndrome (ClinVar).

How common is TFAP2B p.Pro73Arg (c.218C>G) in the general population?

TFAP2B p.Pro73Arg (c.218C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TFAP2B p.Pro73Arg (c.218C>G)?

AlphaMissense predicts likely pathogenic (score 0.9882) — an in-silico prediction, not a clinical call.

TFAP2B p.Pro73Arg

c.218C>G · rs80338910 · VCV8044

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9882 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Char syndrome

Computational evidence

Protein change
AlphaMissense	0.9882	likely pathogenic ✓ concordant with ClinVar
REVEL	0.83	moderately pathogenic-leaning
SaProt	LLR -9.12	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.4, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 17 kb · p 0.49 · regional, not allelic
Overall
CADD	29.9	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 8.47e-05% European (non-Finnish) · 1/1,180,000 alleles

Overall 6.2e-05% 1/1,614,058 alleles · very rare exomes 1/1,461,832 · genomes 0/152,226 · 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: TFAP2B
Protein: p.Pro73Arg
Coding: c.218C>G
MANE Select: NM_003221
dbSNP: rs80338910
Type: single nucleotide variant
Location: chr6:50823543 (GRCh38)
Gene constraint: LOEUF 0.353 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 65.95 · 1 PDB
Residue 73: the 'disordered' region; a UniProt-annotated variant site (in char)

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

Disease context

Char syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TFAP2B p.Arg236His Likely pathogenic ★★ same condition
TFAP2B p.Arg285Gln Pathogenic/Likely pathogenic ★★ same condition
TFAP2B p.Asp31Gly Uncertain significance ★★ ⚠ same condition
TFAP2B p.Ser277Trp Uncertain significance ★★ ⚠ same condition
TFAP2B p.Thr306Met Uncertain significance ★★ ⚠ same condition
TFAP2B p.Ala275Asp Pathogenic ★ same condition
TFAP2B p.Arg300Cys Pathogenic ★ same condition
TFAP2B p.Cys327Ter 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/tfap2b-p-pro73arg (accessed [today's date]).

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