Is TRAF3 p.Ile477Val (c.1429A>G) pathogenic?

TRAF3 p.Ile477Val (c.1429A>G) is classified Uncertain significance in TRAF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-12). AlphaMissense: likely benign (0.1337); Very rare (popmax 0.00133%, afr); Associated with herpes simplex encephalitis, susceptibility to, 3.

What condition is associated with TRAF3 p.Ile477Val (c.1429A>G)?

TRAF3 p.Ile477Val (c.1429A>G) is associated with herpes simplex encephalitis, susceptibility to, 3 (ClinVar).

How common is TRAF3 p.Ile477Val (c.1429A>G) in the general population?

TRAF3 p.Ile477Val (c.1429A>G) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TRAF3 p.Ile477Val (c.1429A>G)?

AlphaMissense predicts likely benign (score 0.1337) — an in-silico prediction, not a clinical call.

TRAF3 p.Ile477Val

c.1429A>G · rs1205003742 · VCV1473841

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1337 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

herpes simplex encephalitis, susceptibility to, 3

Computational evidence

Protein change
AlphaMissense	0.1337	likely benign
REVEL	0.14	moderately benign-leaning
SaProt	LLR -5.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 277 bp · p 1.8e-08 · regional, not allelic
Overall
CADD	16.96	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,054 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,186 alleles · very rare exomes 4/1,461,894 · genomes 0/152,292 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,054
European (non-Finnish)	0.000254%	393,346

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.Ile477Val
Coding: c.1429A>G
MANE Select: NM_145725
dbSNP: rs1205003742
Type: single nucleotide variant
Location: chr14:102905506 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.26 · 10 PDB
Residue 477: 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); a β-strand

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.Ile477= Likely benign ★ 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
TRAF3 p.Arg25Cys 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-ile477val (accessed [today's date]).

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