Is TMPO p.Ala287Pro (c.859G>C) pathogenic?

TMPO p.Ala287Pro (c.859G>C) is classified Benign in TMPO (ClinVar, Multiple submitters, 6 submitters; last evaluated 2022-11-01). Low-frequency (popmax 1.04%, nfe).

How common is TMPO p.Ala287Pro (c.859G>C) in the general population?

TMPO p.Ala287Pro (c.859G>C) is low-frequency (popmax 1.04%, nfe) (gnomAD).

TMPO p.Ala287Pro

c.859G>C · rs7133258 · VCV43693

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.04%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.067	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 3,511 bp · p 0.089 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.04% European (non-Finnish) · 12,300/1,179,108 alleles

Filtering AF 1.03% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.02%

Overall 1.01% 16,298/1,612,944 alleles · low-frequency exomes 14,901/1,460,750 · genomes 1,397/152,194 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	4.54%	22
European (non-Finnish)grpmax	1.04%	96
Remaining individualsnot grpmax-eligible	0.791%	126
Ashkenazi Jewishnot grpmax-eligible	0.737%	136
Admixed American	0.243%	411
South Asian	0.149%	669
African / African-American	0.131%	765
Middle Eastern	0.0496%	2,018

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: TMPO
Protein: p.Ala287Pro
Coding: c.859G>C
MANE Select: NM_001032283
dbSNP: rs7133258
Type: single nucleotide variant
Location: chr12:98544517 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 287: a UniProt-annotated variant site (in); the 'nucleoplasmic' region

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

Similar variants

TMPO c.565+1005A>G Uncertain significance ★★ ⚠ same type
TMPO c.565+1009T>C Uncertain significance ★★ ⚠ same type
TMPO c.565+1012A>C Uncertain significance ★★ ⚠ same type
TMPO c.565+1017A>G Uncertain significance ★★ ⚠ same type
TMPO c.565+1026A>G Uncertain significance ★★ ⚠ same type
TMPO c.565+1029G>T Uncertain significance ★★ ⚠ same type
TMPO c.565+1048G>C Uncertain significance ★★ ⚠ same type
TMPO c.565+1053A>G 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/tmpo-p-ala287pro (accessed [today's date]).

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