Is TPR p.Arg446Cys (c.1336C>T) pathogenic?

TPR p.Arg446Cys (c.1336C>T) is classified Uncertain significance in TPR (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-17). AlphaMissense: likely benign (0.3271); Very rare (popmax 0.00272%, afr).

How common is TPR p.Arg446Cys (c.1336C>T) in the general population?

TPR p.Arg446Cys (c.1336C>T) is very rare (popmax 0.00272%, afr) (gnomAD).

What do computational predictors say about TPR p.Arg446Cys (c.1336C>T)?

AlphaMissense predicts likely benign (score 0.3271) — an in-silico prediction, not a clinical call.

TPR p.Arg446Cys

c.1336C>T · rs1266844942 · VCV2364541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3271 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00272%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.3271	likely benign
REVEL	0.412	indeterminate
SaProt	LLR -10.21	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.26 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.043 · regional, not allelic
Overall
CADD	33.0	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 0.00272% African / African-American · 2/73,632 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000832%

Overall 0.00144% 23/1,599,748 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00272%	36,816
East Asian	0.00224%	44,566
Remaining individualsnot grpmax-eligible	0.00162%	61,884
European (non-Finnish)	0.00161%	61,920

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: TPR
Protein: p.Arg446Cys
Coding: c.1336C>T
MANE Select: NM_003292
dbSNP: rs1266844942
Type: single nucleotide variant
Location: chr1:186359852 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.60 · 4 PDB
Residue 446: the 'necessary for association to the npc' region

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

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TPR p.Leu1314= Benign ★★ same type
TPR p.Pro2168Ser Benign ★★ same type
TPR p.Thr762= Benign ★★ same type
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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/tpr-p-arg446cys (accessed [today's date]).

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