Is TRAFD1 p.Pro474Ala (c.1420C>G) pathogenic?

TRAFD1 p.Pro474Ala (c.1420C>G) is classified Uncertain significance in TRAFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-16). AlphaMissense: likely benign (0.0629); Absent from gnomAD v4.1.

How common is TRAFD1 p.Pro474Ala (c.1420C>G) in the general population?

TRAFD1 p.Pro474Ala (c.1420C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TRAFD1 p.Pro474Ala (c.1420C>G)?

AlphaMissense predicts likely benign (score 0.0629) — an in-silico prediction, not a clinical call.

TRAFD1 p.Pro474Ala

c.1420C>G · rs753181748 · VCV3181805

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0629 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0629	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.67	GERP -4.2
Regional constraint	o/e 0.89	unconstrained · MANE · 22 kb · p 0.0022 · regional, not allelic
Overall
CADD	7.801	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

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: TRAFD1
Protein: p.Pro474Ala
Coding: c.1420C>G
MANE Select: NM_006700
dbSNP: rs753181748
Type: single nucleotide variant
Location: chr12:112151941 (GRCh38)
Gene constraint: LOEUF 0.749 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 58.45 · 1 PDB
Residue 474: the 'disordered' region

Full TRAFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TRAFD1 p.Ala56Thr Uncertain significance ★★ ⚠ same type
TRAFD1 p.Glu232= Benign ★★ same type
TRAFD1 p.Ala147Thr Uncertain significance ★ ⚠ same type
TRAFD1 p.Ala258Thr Uncertain significance ★ ⚠ same type
TRAFD1 p.Ala317Thr Uncertain significance ★ ⚠ same type
TRAFD1 p.Ala505Val Uncertain significance ★ ⚠ same type
TRAFD1 p.Ala554Ser Uncertain significance ★ ⚠ same type
TRAFD1 p.Arg112Trp 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/trafd1-p-pro474ala (accessed [today's date]).

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