Is TRAF3IP1 p.Ser492Pro (c.1474T>C) pathogenic?

TRAF3IP1 p.Ser492Pro (c.1474T>C) is classified Uncertain significance in TRAF3IP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-04). AlphaMissense: likely benign (0.1543); Very rare (popmax 8.48e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with TRAF3IP1 p.Ser492Pro (c.1474T>C)?

TRAF3IP1 p.Ser492Pro (c.1474T>C) is associated with Inborn genetic diseases (ClinVar).

How common is TRAF3IP1 p.Ser492Pro (c.1474T>C) in the general population?

TRAF3IP1 p.Ser492Pro (c.1474T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about TRAF3IP1 p.Ser492Pro (c.1474T>C)?

AlphaMissense predicts likely benign (score 0.1543) — an in-silico prediction, not a clinical call.

TRAF3IP1 p.Ser492Pro

c.1474T>C · rs2469704508 · VCV2616242

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1543 · ACMG-weighted

gnomAD v4.1

Rare

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

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1543	likely benign
REVEL	0.103	moderately benign-leaning
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.26	acceptor loss, 16 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.46	GERP 0.08, phastCons 0.15
Regional constraint	o/e 0.94	unconstrained · MANE · 77 kb · p 0.082 · regional, not allelic
Overall
CADD	11.31	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 8.48e-05% European (non-Finnish) · 1/1,179,374 alleles

Overall 6.2e-05% 1/1,611,618 alleles · very rare exomes 1/1,459,306 · genomes 0/152,312 · 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: TRAF3IP1
Protein: p.Ser492Pro
Coding: c.1474T>C
MANE Select: NM_015650
dbSNP: rs2469704508
Type: single nucleotide variant
Location: chr2:238352849 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.95 · 2 PDB
Residue 492: the 'disordered' region; the 'disc1-interaction domain' region

Full TRAF3IP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

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IFT54 p.Asn503Ser Uncertain significance ★★ ⚠ same condition
IFT54 p.Asp233Asn Uncertain significance ★★ ⚠ same condition
IFT54 p.Ile664Phe Uncertain significance ★★ ⚠ same condition
IFT54 p.Lys304Glu Uncertain significance ★★ ⚠ same condition
IFT54 p.Ser689Leu 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/traf3ip1-p-ser492pro (accessed [today's date]).

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