Is TRAF3 p.Leu409= (c.1227G>A) pathogenic?

TRAF3 p.Leu409= (c.1227G>A) is classified Likely benign in TRAF3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-13). Ultra-rare (popmax 0.0495%, mid); Associated with herpes simplex encephalitis, susceptibility to, 3.

What condition is associated with TRAF3 p.Leu409= (c.1227G>A)?

TRAF3 p.Leu409= (c.1227G>A) is associated with herpes simplex encephalitis, susceptibility to, 3 (ClinVar).

How common is TRAF3 p.Leu409= (c.1227G>A) in the general population?

TRAF3 p.Leu409= (c.1227G>A) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

TRAF3 p.Leu409=

c.1227G>A · rs150483724 · VCV1110501

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

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 -0.75	GERP -4.2
Overall
CADD	5.601	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0495% Middle Eastern · 3/6,062 alleles

Filtering AF 0.0234% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0197%

Overall 0.00551% 89/1,614,224 alleles · ultra-rare exomes 73/1,461,886 · genomes 16/152,338 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,021
Admixed American	0.035%	2,858
Ashkenazi Jewishnot grpmax-eligible	0.027%	3,701
Remaining individualsnot grpmax-eligible	0.0128%	7,814
African / African-American	0.012%	8,341
South Asian	0.00439%	22,773
European (non-Finnish)	0.00297%	33,715
Finnishnot grpmax-eligible	0.00156%	64,032

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.Leu409=
Coding: c.1227G>A
MANE Select: NM_145725
dbSNP: rs150483724
Type: single nucleotide variant
Location: chr14:102905304 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.26 · 10 PDB
Residue 409: 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); an α-helix; the '(microbial infection) interaction with glycoprotein n of andes and new york hantaviruses' region

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.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
TRAF3 p.Arg25Cys Uncertain significance ★★ ⚠ same condition
TRAF3 p.Arg338Gln 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-leu409 (accessed [today's date]).

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