Is TMPO c.565+99A>C pathogenic?

TMPO c.565+99A>C is classified Likely benign in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-16). Rare (popmax 0.727%, nfe).

How common is TMPO c.565+99A>C in the general population?

TMPO c.565+99A>C is rare (popmax 0.727%, nfe) (gnomAD).

TMPO c.565+99A>C

rs187564154 · VCV676582

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.727%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
Splice region	donor +99	deep intronic (+99 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -3.5
Non-coding constraint	Z 0.58	1 kb window · o/e 0.94 · regional · uncalibrated
Overall
CADD	2.877	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.727% European (non-Finnish) · 4,770/655,918 alleles

Filtering AF 0.71% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.703%

Overall 0.641% 6,259/977,134 alleles · rare exomes 5,483/824,764 · genomes 776/152,370 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.4%	71
European (non-Finnish)grpmax	0.727%	138
Amishnot grpmax-eligible	0.658%	152
Ashkenazi Jewishnot grpmax-eligible	0.54%	185
Remaining individualsnot grpmax-eligible	0.488%	205
South Asian	0.332%	301
Admixed American	0.233%	428
Middle Eastern	0.171%	584
African / African-American	0.121%	828
East Asian	0.00518%	19,312

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
Coding: c.565+99A>C
MANE Select: NM_001032283
dbSNP: rs187564154
Type: single nucleotide variant
Location: chr12:98531937 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB

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-c-565-plus-99a-c (accessed [today's date]).

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