Is TRAF3IP1 p.Val125Met (c.373G>A) pathogenic?

TRAF3IP1 p.Val125Met (c.373G>A) is classified Pathogenic in TRAF3IP1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2016-09-06). AlphaMissense: likely pathogenic (0.8202); Very rare (popmax 6.2e-05%); Associated with Senior-Loken syndrome 9.

What condition is associated with TRAF3IP1 p.Val125Met (c.373G>A)?

TRAF3IP1 p.Val125Met (c.373G>A) is associated with Senior-Loken syndrome 9 (ClinVar).

How common is TRAF3IP1 p.Val125Met (c.373G>A) in the general population?

TRAF3IP1 p.Val125Met (c.373G>A) is very rare (popmax 6.2e-05%) (gnomAD).

How is Senior-Loken syndrome inherited?

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

What do computational predictors say about TRAF3IP1 p.Val125Met (c.373G>A)?

AlphaMissense predicts likely pathogenic (score 0.8202) — an in-silico prediction, not a clinical call.

TRAF3IP1 p.Val125Met

c.373G>A · rs886037898 · VCV254149

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8202 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.2e-05%)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Senior-Loken syndrome 9

Computational evidence

Protein change
AlphaMissense	0.8202	likely pathogenic ✓ concordant with ClinVar
REVEL	0.445	indeterminate
SaProt	LLR -13.21	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 77 kb · p 0.082 · regional, not allelic
Overall
CADD	24.4	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 6.2e-05%

Overall 6.2e-05% 1/1,613,918 alleles · very rare exomes 1/1,461,736 · genomes 0/152,182 · 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.Val125Met
Coding: c.373G>A
MANE Select: NM_015650
dbSNP: rs886037898
Type: single nucleotide variant
Location: chr2:238328704 (GRCh38)
Gene constraint: LOEUF 0.723 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 61.95 · 2 PDB
Residue 125: the 'abolishes microtubules-binding when missing' region; a UniProt-annotated variant site (in slsn9; results in altered folding of the n-terminus; does not affect interaction with ift20; loss of interaction with map4); a UniProt-annotated variant site (in slsn9; results in altered folding of the n-terminus; does not localize to the ciliary tip and transition zone; does not affect interaction with ift20; loss of interaction with map4); an α-helix

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

Disease context

Senior-Loken syndrome 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Senior-Loken syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Adolescent, Adult, Childhood, Infancy
Prevalence: 1-9 / 1 000 000 (Worldwide)

Similar variants

TRAF3IP1 p.Val125Ala Uncertain significance ★ ⚠ same residue
IFT54 p.Arg565Ter Pathogenic/Likely pathogenic ★★ same condition
IFT54 p.Gly355Glu Uncertain significance ★★ ⚠ same condition
IFT54 p.Pro30Ser Uncertain significance ★★ ⚠ same condition
TRAF3IP1 p.Arg271Gln Uncertain significance ★★ ⚠ same condition
TRAF3IP1 p.Arg271Trp Uncertain significance ★★ ⚠ same condition
TRAF3IP1 p.Arg470Trp Uncertain significance ★★ ⚠ same condition
TRAF3IP1 p.Glu229Lys 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-val125met (accessed [today's date]).

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