Is TPR p.Arg441His (c.1322G>A) pathogenic?

TPR p.Arg441His (c.1322G>A) is classified Uncertain significance in TPR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-24). AlphaMissense: likely benign (0.2511); Very rare (popmax 0.00405%, afr).

How common is TPR p.Arg441His (c.1322G>A) in the general population?

TPR p.Arg441His (c.1322G>A) is very rare (popmax 0.00405%, afr) (gnomAD).

What do computational predictors say about TPR p.Arg441His (c.1322G>A)?

AlphaMissense predicts likely benign (score 0.2511) — an in-silico prediction, not a clinical call.

TPR p.Arg441His

c.1322G>A · rs1209080251 · VCV3181586

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2511 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00405%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2511	likely benign
REVEL	0.284	benign-leaning
SaProt	LLR -7.92	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 7.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.043 · regional, not allelic
Overall
CADD	29.6	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 0.00405% African / African-American · 3/74,032 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000788%

Overall 0.0015% 24/1,604,652 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00405%	24,677
Admixed American	0.00351%	28,511
European (non-Finnish)	0.00153%	65,428
South Asian	0.00113%	88,864

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.Arg441His
Coding: c.1322G>A
MANE Select: NM_003292
dbSNP: rs1209080251
Type: single nucleotide variant
Location: chr1:186359866 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.60 · 4 PDB
Residue 441: the 'necessary for association to the npc' region

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

Similar variants

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TPR p.Arg467= Benign/Likely benign ★★ same type
TPR p.Leu1314= Benign ★★ same type
TPR p.Pro2168Ser Benign ★★ same type
TPR p.Thr762= Benign ★★ same type
TPR c.2610+5G>A Uncertain significance ★ same type
TPR p.Ala1025Thr 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/tpr-p-arg441his (accessed [today's date]).

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