Is TNFAIP3 p.Leu725= (c.2175G>A) pathogenic?

TNFAIP3 p.Leu725= (c.2175G>A) is classified Benign/Likely benign in TNFAIP3 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-04-02). Rare (popmax 0.281%, nfe); Associated with autoinflammatory syndrome, familial, Behcet-like 1.

What condition is associated with TNFAIP3 p.Leu725= (c.2175G>A)?

TNFAIP3 p.Leu725= (c.2175G>A) is associated with autoinflammatory syndrome, familial, Behcet-like 1 (ClinVar).

How common is TNFAIP3 p.Leu725= (c.2175G>A) in the general population?

TNFAIP3 p.Leu725= (c.2175G>A) is rare (popmax 0.281%, nfe) (gnomAD).

TNFAIP3 p.Leu725=

c.2175G>A · rs140354477 · VCV711037

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

rare (popmax 0.281%, nfe)

Conditions

autoinflammatory syndrome, familial, Behcet-like 1

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 5.1	GERP 1.6, phastCons 1
Overall
CADD	9.066	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.281% European (non-Finnish) · 3,313/1,179,990 alleles

Filtering AF 0.273% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.27%

Overall 0.259% 4,183/1,613,870 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.672%	149
Ashkenazi Jewishnot grpmax-eligible	0.618%	162
European (non-Finnish)grpmax	0.281%	356
Remaining individualsnot grpmax-eligible	0.219%	456
Admixed American	0.115%	870
African / African-American	0.0547%	1,828
Middle Eastern	0.033%	3,030
South Asian	0.00879%	11,382

Finnish 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.Leu725=
Coding: c.2175G>A
MANE Select: NM_001270508
dbSNP: rs140354477
Type: single nucleotide variant
Location: chr6:137881121 (GRCh38)
Gene constraint: LOEUF 0.209 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.86 · 17 PDB
Residue 725: the 'interaction with tnip1' region; the 'sufficient for inhibitory activity of tnf-induced nf-kappa-b activity' region; the 'required for lysosomal localization and for traf2 lysosomal degradation' region

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

Disease context

autoinflammatory syndrome, familial, Behcet-like 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TNFAIP3 p.Arg271Ter Pathogenic ★★ same condition
TNFAIP3 p.Arg87Ter Pathogenic ★★ same condition
TNFAIP3 p.Glu366Ter Pathogenic/Likely pathogenic ★★ same condition
TNFAIP3 p.Ala717Thr Uncertain significance ★★ ⚠ same condition
TNFAIP3 p.Arg439Gln Uncertain significance ★★ ⚠ same condition
TNFAIP3 p.Arg569Gln Uncertain significance ★★ ⚠ same condition
TNFAIP3 p.Arg61Trp Uncertain significance ★★ same condition
TNFAIP3 p.Arg660Lys 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/tnfaip3-p-leu725 (accessed [today's date]).

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