Is TPR p.Pro2168Ser (c.6502C>T) pathogenic?

TPR p.Pro2168Ser (c.6502C>T) is classified Benign in TPR (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-03-29). AlphaMissense: likely benign (0.1492); Common (popmax 5.84%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about TPR p.Pro2168Ser (c.6502C>T)?

AlphaMissense predicts likely benign (score 0.1492) — an in-silico prediction, not a clinical call.

TPR p.Pro2168Ser

Q: How common is TPR p.Pro2168Ser (c.6502C>T) in the general population?

TPR p.Pro2168Ser (c.6502C>T) is common (popmax 5.84%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6502C>T · rs183345967 · VCV782687

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1492 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 5.84%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1492	likely benign
REVEL	0.108	moderately benign-leaning
SaProt	LLR -5.09	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 12	GERP 1.6, phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 4,038 bp · p 3.1e-11 · regional, not allelic
Overall
CADD	26.7	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 5.84% Admixed American · 3,493/59,806 alleles

Filtering AF 5.68% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.61%

Overall 0.234% 3,774/1,612,620 alleles · common exomes 2,986/1,460,468 · genomes 788/152,152 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	5.84%	17
Remaining individualsnot grpmax-eligible	0.178%	563
East Asian	0.123%	815
African / African-American	0.1%	1,000
European (non-Finnish)	0.00339%	29,479

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.Pro2168Ser
Coding: c.6502C>T
MANE Select: NM_003292
dbSNP: rs183345967
Type: single nucleotide variant
Location: chr1:186320378 (GRCh38)
Gene constraint: LOEUF 0.203 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 61.60 · 4 PDB

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

Similar variants

TPR p.Thr1751Ala Uncertain significance ★★ ⚠ same type
TPR p.Arg1832His Likely benign ★★ same type
TPR p.Arg467= Benign/Likely benign ★★ same type
TPR p.Leu1314= 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
TPR p.Ala1312Thr 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-pro2168ser (accessed [today's date]).

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