Is TRAF3IP2 p.Arg449Ser (c.1345C>A) pathogenic?

TRAF3IP2 p.Arg449Ser (c.1345C>A) is classified Uncertain significance in TRAF3IP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-18). AlphaMissense: likely pathogenic (0.7376); Absent from gnomAD v4.1; Associated with candidiasis, familial, 8.

What condition is associated with TRAF3IP2 p.Arg449Ser (c.1345C>A)?

TRAF3IP2 p.Arg449Ser (c.1345C>A) is associated with candidiasis, familial, 8 (ClinVar).

How common is TRAF3IP2 p.Arg449Ser (c.1345C>A) in the general population?

TRAF3IP2 p.Arg449Ser (c.1345C>A) is absent from gnomAD v4.1 (gnomAD).

How is Chronic mucocutaneous candidiasis inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about TRAF3IP2 p.Arg449Ser (c.1345C>A)?

AlphaMissense predicts likely pathogenic (score 0.7376) — an in-silico prediction, not a clinical call.

TRAF3IP2 p.Arg449Ser

c.1345C>A · rs200246882 · VCV2146139

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7376 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

candidiasis, familial, 8

Computational evidence

Protein change
AlphaMissense	0.7376	likely pathogenic
REVEL	0.218	benign-leaning
SaProt	LLR -6.67	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 14 kb · p 3.2e-08 · regional, not allelic
Overall
CADD	28.2	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R458S vs ClinVar R449S) — verify the residue.

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: TRAF3IP2
Protein: p.Arg449Ser
Coding: c.1345C>A
MANE Select: NM_147686
dbSNP: rs200246882
Type: single nucleotide variant
Location: chr6:111567638 (GRCh38)
Gene constraint: LOEUF 0.771 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 53.91 · 1 PDB
Residue 458 UniProt numbering: the sefir domain

Full TRAF3IP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

candidiasis, familial, 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Chronic mucocutaneous candidiasis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy

Similar variants

TRAF3IP2 p.Arg449Cys Uncertain significance ★ ⚠ same residue
TRAF3IP2 p.Arg449His Uncertain significance ★ ⚠ same residue
TRAF3IP2 c.1201+1G>C Likely pathogenic ★★ same condition
TRAF3IP2 p.Ala328Thr Uncertain significance ★★ ⚠ same condition
TRAF3IP2 p.Ala36Val Uncertain significance ★★ ⚠ same condition
TRAF3IP2 p.Ala473Thr Uncertain significance ★★ ⚠ same condition
TRAF3IP2 p.Asn45Lys Uncertain significance ★★ ⚠ same condition
TRAF3IP2 p.Gln18His 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/traf3ip2-p-arg449ser (accessed [today's date]).

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