Is TRAF3IP2 p.Pro253Arg (c.758C>G) pathogenic?

TRAF3IP2 p.Pro253Arg (c.758C>G) is classified Uncertain significance in TRAF3IP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-08). AlphaMissense: likely benign (0.0948); Ultra-rare (popmax 0.0338%, amr); Associated with candidiasis, familial, 8.

What condition is associated with TRAF3IP2 p.Pro253Arg (c.758C>G)?

TRAF3IP2 p.Pro253Arg (c.758C>G) is associated with candidiasis, familial, 8 (ClinVar).

How common is TRAF3IP2 p.Pro253Arg (c.758C>G) in the general population?

TRAF3IP2 p.Pro253Arg (c.758C>G) is ultra-rare (popmax 0.0338%, amr) (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.Pro253Arg (c.758C>G)?

AlphaMissense predicts likely benign (score 0.0948) — an in-silico prediction, not a clinical call.

TRAF3IP2 p.Pro253Arg

c.758C>G · rs146627823 · VCV541098

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0948 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0338%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

candidiasis, familial, 8

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.0948	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -7.16	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.78	GERP -1.1, phastCons 0.14
Regional constraint	o/e 0.86	unconstrained · MANE · 19 kb · p 0.0015 · regional, not allelic
Overall
CADD	10.67	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P262R vs ClinVar P253R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0338% Admixed American · 15/44,402 alleles

Filtering AF 0.0208% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0176%

Overall 0.0168% 256/1,519,800 alleles · ultra-rare exomes 233/1,367,522 · genomes 23/152,278 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0338%	2,960
European (non-Finnish)	0.0206%	4,854
African / African-American	0.00557%	17,951
Remaining individualsnot grpmax-eligible	0.00343%	29,179
Finnishnot grpmax-eligible	0.00165%	60,614

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: TRAF3IP2
Protein: p.Pro253Arg
Coding: c.758C>G
MANE Select: NM_147686
dbSNP: rs146627823
Type: single nucleotide variant
Location: chr6:111591329 (GRCh38)

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

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-pro253arg (accessed [today's date]).

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