Is TRAF3 p.Pro489= (c.1467G>A) pathogenic?

TRAF3 p.Pro489= (c.1467G>A) is classified Likely benign in TRAF3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-09-30). Ultra-rare (popmax 0.02%, amr); Associated with herpes simplex encephalitis, susceptibility to, 3.

What condition is associated with TRAF3 p.Pro489= (c.1467G>A)?

TRAF3 p.Pro489= (c.1467G>A) is associated with herpes simplex encephalitis, susceptibility to, 3 (ClinVar).

How common is TRAF3 p.Pro489= (c.1467G>A) in the general population?

TRAF3 p.Pro489= (c.1467G>A) is ultra-rare (popmax 0.02%, amr) (gnomAD).

TRAF3 p.Pro489=

c.1467G>A · rs761788321 · VCV2768017

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Conditions

herpes simplex encephalitis, susceptibility to, 3

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 -7.1	GERP -3.9
Overall
CADD	0.79	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/60,000 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00254% 41/1,614,026 alleles · ultra-rare exomes 30/1,461,892 · genomes 11/152,134 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,000
East Asian	0.00891%	11,224
European (non-Finnish)	0.00186%	53,638
Remaining individualsnot grpmax-eligible	0.0016%	62,488
Finnishnot grpmax-eligible	0.00156%	64,018
African / African-American	0.00134%	74,904

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: TRAF3
Protein: p.Pro489=
Coding: c.1467G>A
MANE Select: NM_145725
dbSNP: rs761788321
Type: single nucleotide variant
Location: chr14:102905544 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.26 · 10 PDB
Residue 489: the math domain; a UniProt-annotated variant site (in imd132b; likely pathogenic; decreased traf3 mrna and protein levels and absence of a truncated traf3 protein in patient cells); a UniProt-annotated variant site (in imd132b; likely pathogenic)

Full TRAF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

herpes simplex encephalitis, susceptibility to, 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TRAF3 p.Pro489Leu Uncertain significance ★ ⚠ same residue
TRAF3 p.Pro489delinsLeuProTrp Uncertain significance ★ same residue
TRAF3 p.Trp344Ter Pathogenic ★★ same condition
TRAF3 p.Ala188Val Uncertain significance ★★ ⚠ same condition
TRAF3 p.Ala371Thr Uncertain significance ★★ ⚠ same condition
TRAF3 p.Ala371Val Uncertain significance ★★ ⚠ same condition
TRAF3 p.Ala78Val Uncertain significance ★★ ⚠ same condition
TRAF3 p.Ala90Val 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/traf3-p-pro489 (accessed [today's date]).

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