Is TNFAIP3 p.Pro752Ser (c.2254C>T) pathogenic?

TNFAIP3 p.Pro752Ser (c.2254C>T) is classified Likely benign in TNFAIP3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.0758); Rare (popmax 0.191%, afr).

How common is TNFAIP3 p.Pro752Ser (c.2254C>T) in the general population?

TNFAIP3 p.Pro752Ser (c.2254C>T) is rare (popmax 0.191%, afr) (gnomAD).

What do computational predictors say about TNFAIP3 p.Pro752Ser (c.2254C>T)?

AlphaMissense predicts likely benign (score 0.0758) — an in-silico prediction, not a clinical call.

TNFAIP3 p.Pro752Ser

c.2254C>T · rs138068339 · VCV1606274

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0758 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.191%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0758	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -6.62	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.32	gain · loss 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 2.7	GERP 0.62, phastCons 0.28
Regional constraint	o/e 0.89	unconstrained · MANE · 4,184 bp · p 0.0057 · regional, not allelic
Overall
CADD	13.57	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 0.191% African / African-American · 143/74,988 alleles

Filtering AF 0.165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.155%

Overall 0.0093% 150/1,613,292 alleles · rare exomes 78/1,461,154 · genomes 72/152,138 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.191%	524
Remaining individualsnot grpmax-eligible	0.0064%	15,621
Admixed American	0.00167%	59,936
European (non-Finnish)	0.00017%	589,880

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.Pro752Ser
Coding: c.2254C>T
MANE Select: NM_001270508
dbSNP: rs138068339
Type: single nucleotide variant
Location: chr6:137881200 (GRCh38)
Gene constraint: LOEUF 0.209 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.86 · 17 PDB
Residue 752: 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

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-pro752ser (accessed [today's date]).

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