Is TRAK1 p.Arg552Ser (c.1654C>A) pathogenic?

TRAK1 p.Arg552Ser (c.1654C>A) is classified Uncertain significance in TRAK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely benign (0.1404); Very rare (popmax 0.00133%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRAK1 p.Arg552Ser (c.1654C>A)?

TRAK1 p.Arg552Ser (c.1654C>A) is associated with Inborn genetic diseases (ClinVar).

How common is TRAK1 p.Arg552Ser (c.1654C>A) in the general population?

TRAK1 p.Arg552Ser (c.1654C>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about TRAK1 p.Arg552Ser (c.1654C>A)?

AlphaMissense predicts likely benign (score 0.1404) — an in-silico prediction, not a clinical call.

TRAK1 p.Arg552Ser

c.1654C>A · VCV4189875

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1404 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1404	likely benign
REVEL	0.156	moderately benign-leaning
SaProt	LLR -5.47	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 2.1, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 111 kb · p 0.024 · regional, not allelic
Overall
CADD	21.1	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 0.00133% African / African-American · 1/74,940 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,330 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,940
European (non-Finnish)	0.00017%	589,741

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: TRAK1
Protein: p.Arg552Ser
Coding: c.1654C>A
MANE Select: NM_001042646
Type: single nucleotide variant
Location: chr3:42202662 (GRCh38)
Gene constraint: LOEUF 0.461 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 59.19

Full TRAK1 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

TRAK1 p.Arg552Cys Uncertain significance ★★ ⚠ same residue
TRAK1 p.Ala334Thr Uncertain significance ★★ ⚠ same condition
TRAK1 p.Ala498Val Uncertain significance ★★ ⚠ same condition
TRAK1 p.Ala655Val Uncertain significance ★★ ⚠ same condition
TRAK1 p.Ala861Thr Uncertain significance ★★ ⚠ same condition
TRAK1 p.Arg165Gln Uncertain significance ★★ ⚠ same condition
TRAK1 p.Arg279Cys Uncertain significance ★★ same condition
TRAK1 p.Arg534His 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/trak1-p-arg552ser (accessed [today's date]).

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