Is TRAF3 p.Val558Asp (c.1673T>A) pathogenic?

TRAF3 p.Val558Asp (c.1673T>A) is classified Uncertain significance in TRAF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1.

How common is TRAF3 p.Val558Asp (c.1673T>A) in the general population?

TRAF3 p.Val558Asp (c.1673T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRAF3 p.Val558Asp (c.1673T>A)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

TRAF3 p.Val558Asp

c.1673T>A · VCV4189773

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 4% in TRAF3
REVEL	0.688	pathogenic-leaning
SaProt	LLR -15.62	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.49	unconstrained · MANE · 277 bp · p 1.8e-08 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TRAF3
Protein: p.Val558Asp
Coding: c.1673T>A
MANE Select: NM_145725
Type: single nucleotide variant
Location: chr14:102905750 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.26 · 10 PDB
Residue 558: 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

Similar variants

TRAF3 p.Trp344Ter Pathogenic ★★ same type
TRAF3 p.Ala188Val Uncertain significance ★★ ⚠ same type
TRAF3 p.Ala371Thr Uncertain significance ★★ ⚠ same type
TRAF3 p.Ala371Val Uncertain significance ★★ ⚠ same type
TRAF3 p.Ala78Val Uncertain significance ★★ ⚠ same type
TRAF3 p.Ala90Val Uncertain significance ★★ ⚠ same type
TRAF3 p.Arg25Cys Uncertain significance ★★ ⚠ same type
TRAF3 p.Arg338Gln Uncertain significance ★★ ⚠ same type

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-val558asp (accessed [today's date]).

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