Is TRAF6 p.His421Gln (c.1263C>G) pathogenic?

TRAF6 p.His421Gln (c.1263C>G) is classified Uncertain significance in TRAF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.2175); Very rare (popmax 8.47e-05%, nfe).

How common is TRAF6 p.His421Gln (c.1263C>G) in the general population?

TRAF6 p.His421Gln (c.1263C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TRAF6 p.His421Gln (c.1263C>G)?

AlphaMissense predicts likely benign (score 0.2175) — an in-silico prediction, not a clinical call.

TRAF6 p.His421Gln

c.1263C>G · VCV4189833

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2175 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2175	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -4.82	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 1.9	GERP 1.1, phastCons 1
Regional constraint	o/e 0.37	unconstrained · MANE · 453 bp · p 8.3e-19 · regional, not allelic
Overall
CADD	16.1	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 8.47e-05% European (non-Finnish) · 1/1,180,036 alleles

Overall 6.84e-05% 1/1,461,894 alleles · very rare

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: TRAF6
Protein: p.His421Gln
Coding: c.1263C>G
MANE Select: NM_004620
Type: single nucleotide variant
Location: chr11:36490144 (GRCh38)
Gene constraint: LOEUF 0.356 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.30 · 13 PDB
Residue 421: the math domain; the 'interaction with tank' region; an α-helix

Full TRAF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRAF6 p.Ala194Thr Uncertain significance ★ ⚠ same type
TRAF6 p.Arg167His Uncertain significance ★ ⚠ same type
TRAF6 p.Arg402His Uncertain significance ★ same type
TRAF6 p.Asn212Ser Uncertain significance ★ ⚠ same type
TRAF6 p.Asp181Ala Uncertain significance ★ ⚠ same type
TRAF6 p.Glu114Asp Uncertain significance ★ ⚠ same type
TRAF6 p.Glu144Lys Uncertain significance ★ ⚠ same type
TRAF6 p.Glu225Gln 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/traf6-p-his421gln (accessed [today's date]).

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