Is TRAF3 p.Val408= (c.1224C>G) pathogenic?

TRAF3 p.Val408= (c.1224C>G) is classified Benign in TRAF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). Rare (popmax 0.265%, afr); Associated with herpes simplex encephalitis, susceptibility to, 3.

What condition is associated with TRAF3 p.Val408= (c.1224C>G)?

TRAF3 p.Val408= (c.1224C>G) is associated with herpes simplex encephalitis, susceptibility to, 3 (ClinVar).

How common is TRAF3 p.Val408= (c.1224C>G) in the general population?

TRAF3 p.Val408= (c.1224C>G) is rare (popmax 0.265%, afr) (gnomAD).

TRAF3 p.Val408=

c.1224C>G · rs140423891 · VCV1165594

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.265%, afr)

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 -0.84	GERP -4.2, phastCons 0.002
Overall
CADD	3.013	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.265% African / African-American · 199/75,052 alleles

Filtering AF 0.235% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.223%

Overall 0.014% 226/1,614,210 alleles · rare exomes 104/1,461,884 · genomes 122/152,326 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.265%	377
Remaining individualsnot grpmax-eligible	0.0192%	5,209
Admixed American	0.0183%	5,457
Middle Eastern	0.0165%	6,062
South Asian	0.0011%	91,090
European (non-Finnish)	0.000169%	590,019

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.Val408=
Coding: c.1224C>G
MANE Select: NM_145725
dbSNP: rs140423891
Type: single nucleotide variant
Location: chr14:102905301 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.26 · 10 PDB
Residue 408: 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-val408 (accessed [today's date]).

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