Is TRAF3 p.Asp551Glu (c.1653T>A) pathogenic?

TRAF3 p.Asp551Glu (c.1653T>A) is classified Uncertain significance in TRAF3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-11). AlphaMissense: ambiguous (0.415); Very rare (popmax 8.48e-05%, nfe).

How common is TRAF3 p.Asp551Glu (c.1653T>A) in the general population?

TRAF3 p.Asp551Glu (c.1653T>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TRAF3 p.Asp551Glu (c.1653T>A)?

AlphaMissense predicts ambiguous (score 0.415) — an in-silico prediction, not a clinical call.

TRAF3 p.Asp551Glu

c.1653T>A · VCV4865895

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.415 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.415	ambiguous
REVEL	0.262	benign-leaning
SaProt	LLR -8.33	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.049	GERP -1.1, phastCons 0.88
Regional constraint	o/e 0.49	unconstrained · MANE · 277 bp · p 1.8e-08 · regional, not allelic
Overall
CADD	18.93	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,290 alleles

Overall 6.2e-05% 1/1,612,798 alleles · very rare exomes 1/1,460,488 · genomes 0/152,310 · joint denominator

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.Asp551Glu
Coding: c.1653T>A
MANE Select: NM_145725
Type: single nucleotide variant
Location: chr14:102905730 (GRCh38)
Gene constraint: LOEUF 0.321 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 88.26 · 10 PDB
Residue 551: 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)

Full TRAF3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRAF3 p.Asp551Asn Uncertain significance ★ ⚠ same residue
TRAF3 p.Asp551= Likely benign ★ same residue
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

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-asp551glu (accessed [today's date]).

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