Is TRAF3 p.Ala12= (c.36G>A) pathogenic?

TRAF3 p.Ala12= (c.36G>A) is classified Likely benign in TRAF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-10). Very rare (popmax 0.00822%, nfe); Associated with herpes simplex encephalitis, susceptibility to, 3.

What condition is associated with TRAF3 p.Ala12= (c.36G>A)?

TRAF3 p.Ala12= (c.36G>A) is associated with herpes simplex encephalitis, susceptibility to, 3 (ClinVar).

How common is TRAF3 p.Ala12= (c.36G>A) in the general population?

TRAF3 p.Ala12= (c.36G>A) is very rare (popmax 0.00822%, nfe) (gnomAD).

TRAF3 p.Ala12=

c.36G>A · rs199639339 · VCV723895

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00822%, nfe)

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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -4.2	GERP -3.5
Overall
CADD	0.488	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00822% European (non-Finnish) · 97/1,179,974 alleles

Filtering AF 0.00689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.00632% 102/1,614,028 alleles · very rare exomes 93/1,461,818 · genomes 9/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00822%	12,165
Remaining individualsnot grpmax-eligible	0.0048%	20,835
East Asian	0.00223%	44,874
African / African-American	0.00133%	75,012

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.Ala12=
Coding: c.36G>A
MANE Select: NM_145725
dbSNP: rs199639339
Type: single nucleotide variant
Location: chr14:102870237 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.26 · 10 PDB
Residue 12: the 'disordered' 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.Ala12Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
TRAF3 p.Ala12Val 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-ala12 (accessed [today's date]).

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