Is TMPO p.Arg48Cys (c.142C>T) pathogenic?

TMPO p.Arg48Cys (c.142C>T) is classified Uncertain significance in TMPO (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-09). AlphaMissense: ambiguous (0.5491); Very rare (popmax 0.00267%, afr).

How common is TMPO p.Arg48Cys (c.142C>T) in the general population?

TMPO p.Arg48Cys (c.142C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about TMPO p.Arg48Cys (c.142C>T)?

AlphaMissense predicts ambiguous (score 0.5491) — an in-silico prediction, not a clinical call.

TMPO p.Arg48Cys

c.142C>T · VCV3458760

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5491 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
AlphaMissense	0.5491	ambiguous
REVEL	0.341	indeterminate
SaProt	LLR -9.90	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.2	GERP 2.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 28 kb · p 0.89 · 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 0.00267% African / African-American · 2/74,918 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000249% 4/1,609,430 alleles · very rare exomes 3/1,457,226 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,459
European (non-Finnish)	0.00017%	589,518

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.Arg48Cys
Coding: c.142C>T
MANE Select: NM_001032283
Type: single nucleotide variant
Location: chr12:98516009 (GRCh38)
Gene constraint: LOEUF 0.736 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 60.49 · 14 PDB
Residue 48: the lem-like domain; a turn; the 'disordered' region; the 'nucleoplasmic' region

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

Similar variants

TMPO p.Arg48= Likely benign ★ same residue
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

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-arg48cys (accessed [today's date]).

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