Is TRAIP p.Arg436Cys (c.1306C>T) pathogenic?

TRAIP p.Arg436Cys (c.1306C>T) is classified Uncertain significance in TRAIP (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-26). AlphaMissense: likely benign (0.0991); Very rare (popmax 0.004%, afr); Associated with Inborn genetic diseases.

What condition is associated with TRAIP p.Arg436Cys (c.1306C>T)?

TRAIP p.Arg436Cys (c.1306C>T) is associated with Inborn genetic diseases, Seckel syndrome 9 (ClinVar).

How common is TRAIP p.Arg436Cys (c.1306C>T) in the general population?

TRAIP p.Arg436Cys (c.1306C>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about TRAIP p.Arg436Cys (c.1306C>T)?

AlphaMissense predicts likely benign (score 0.0991) — an in-silico prediction, not a clinical call.

TRAIP p.Arg436Cys

c.1306C>T · rs536675100 · VCV587459

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0991 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0991	likely benign
REVEL	0.271	benign-leaning
SaProt	LLR -8.23	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 6.3	GERP 0.26, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 27 kb · p 4.3e-05 · regional, not allelic
Overall
CADD	29.9	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 0.004% African / African-American · 3/74,922 alleles

Filtering AF 0.00153% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00192% 31/1,614,094 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,974
Remaining individualsnot grpmax-eligible	0.0032%	31,242
European (non-Finnish)	0.0022%	45,387

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: TRAIP
Protein: p.Arg436Cys
Coding: c.1306C>T
MANE Select: NM_005879
dbSNP: rs536675100
Type: single nucleotide variant
Location: chr3:49829207 (GRCh38)
Gene constraint: LOEUF 0.739 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.24 · 1 PDB
Residue 436: the 'interaction with cyld' region

Full TRAIP 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

Also linked: Seckel syndrome 9

Similar variants

TRAIP p.Arg436His Uncertain significance ★★ ⚠ same residue
TRAIP p.Asp244His Uncertain significance ★★ ⚠ same condition
TRAIP p.Asp431Gly Uncertain significance ★★ ⚠ same condition
TRAIP p.Gln36Arg Uncertain significance ★★ ⚠ same condition
TRAIP p.Glu209Lys Uncertain significance ★★ same condition
TRAIP p.Gly421Ser Uncertain significance ★★ ⚠ same condition
TRAIP p.Ile104Met Uncertain significance ★★ ⚠ same condition
TRAIP p.Leu340Phe 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/traip-p-arg436cys (accessed [today's date]).

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