Is TFAP2A p.Pro99Ser (c.295C>T) pathogenic?

TFAP2A p.Pro99Ser (c.295C>T) is classified Uncertain significance in TFAP2A (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-09). AlphaMissense: likely benign (0.1173); Very rare (popmax 0.00856%, nfe).

How common is TFAP2A p.Pro99Ser (c.295C>T) in the general population?

TFAP2A p.Pro99Ser (c.295C>T) is very rare (popmax 0.00856%, nfe) (gnomAD).

What do computational predictors say about TFAP2A p.Pro99Ser (c.295C>T)?

AlphaMissense predicts likely benign (score 0.1173) — an in-silico prediction, not a clinical call.

TFAP2A p.Pro99Ser

c.295C>T · rs746489683 · VCV2726127

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1173 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00856%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1173	likely benign
REVEL	0.454	indeterminate
SaProt	LLR -6.42	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.88	unconstrained · MANE · 10 kb · p 0.045 · regional, not allelic
Overall
CADD	26.9	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 P97S vs ClinVar P99S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00856% European (non-Finnish) · 101/1,179,862 alleles

Filtering AF 0.00716% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00668%

Overall 0.00626% 101/1,612,938 alleles · very rare exomes 101/1,460,752 · genomes 0/152,186 · 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: TFAP2A
Protein: p.Pro99Ser
Coding: c.295C>T
MANE Select: NM_001372066
dbSNP: rs746489683
Type: single nucleotide variant
Location: chr6:10410092 (GRCh38)
Gene constraint: LOEUF 0.334 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 67.76 · 3 PDB
Residue 97 UniProt numbering: the 'disordered' region

Full TFAP2A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TFAP2A p.Pro99Leu Uncertain significance ★ ⚠ same residue
TFAP2A p.Pro99= Likely benign ★ same residue
TFAP2A p.Ala258Val Pathogenic/Likely pathogenic ★★ same type
TFAP2A p.Arg239Gln Pathogenic/Likely pathogenic ★★ same type
TFAP2A p.Arg325Ter Pathogenic ★★ same type
TFAP2A p.Gln32Ter Likely pathogenic ★★ same type
TFAP2A p.Glu235Lys Likely pathogenic ★★ same type
TFAP2A p.His386Tyr Likely pathogenic ★★ 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/tfap2a-p-pro99ser (accessed [today's date]).

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