Is TNFAIP3 p.Pro576= (c.1728G>A) pathogenic?

TNFAIP3 p.Pro576= (c.1728G>A) is classified Benign/Likely benign in TNFAIP3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-23). Ultra-rare (popmax 0.0425%, nfe).

How common is TNFAIP3 p.Pro576= (c.1728G>A) in the general population?

TNFAIP3 p.Pro576= (c.1728G>A) is ultra-rare (popmax 0.0425%, nfe) (gnomAD).

TNFAIP3 p.Pro576=

c.1728G>A · rs140120540 · VCV1599397

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0425%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.7	GERP -5.4
Overall
CADD	0.083	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0425% European (non-Finnish) · 502/1,180,024 alleles

Filtering AF 0.0394% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0382%

Overall 0.0376% 607/1,613,826 alleles · ultra-rare exomes 570/1,461,742 · genomes 37/152,084 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.159%	630
Remaining individualsnot grpmax-eligible	0.056%	1,785
European (non-Finnish)grpmax	0.0425%	2,351
Middle Eastern	0.0329%	3,042
South Asian	0.0121%	8,280
Admixed American	0.00667%	14,997
African / African-American	0.00534%	18,722
Finnishnot grpmax-eligible	0.00313%	31,936

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TNFAIP3
Protein: p.Pro576=
Coding: c.1728G>A
MANE Select: NM_001270508
dbSNP: rs140120540
Type: single nucleotide variant
Location: chr6:137879173 (GRCh38)
Gene constraint: LOEUF 0.209 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.86 · 17 PDB
Residue 576: the 'interaction with tnip1' region; the 'disordered' region

Full TNFAIP3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TNFAIP3 p.Arg271Ter Pathogenic ★★ same type
TNFAIP3 p.Arg87Ter Pathogenic ★★ same type
TNFAIP3 p.Glu366Ter Pathogenic/Likely pathogenic ★★ same type
TNFAIP3 p.Glu630Ter Pathogenic/Likely pathogenic ★★ same type
TNFAIP3 p.Trp317Ter Pathogenic/Likely pathogenic ★★ same type
TNFAIP3 p.Ala327Val Uncertain significance ★★ ⚠ same type
TNFAIP3 p.Ala586Val Uncertain significance ★★ ⚠ same type
TNFAIP3 p.Ala610Thr 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/tnfaip3-p-pro576 (accessed [today's date]).

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