Is TOMM22 p.Leu135Pro (c.404T>C) pathogenic?

TOMM22 p.Leu135Pro (c.404T>C) is classified Uncertain significance in TOMM22 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-17). AlphaMissense: ambiguous (0.501); Very rare (popmax 8.47e-05%, nfe).

How common is TOMM22 p.Leu135Pro (c.404T>C) in the general population?

TOMM22 p.Leu135Pro (c.404T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about TOMM22 p.Leu135Pro (c.404T>C)?

AlphaMissense predicts ambiguous (score 0.501) — an in-silico prediction, not a clinical call.

TOMM22 p.Leu135Pro

c.404T>C · rs1429439009 · VCV2476180

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.501 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.501	ambiguous
REVEL	0.193	benign-leaning
SaProt	LLR -6.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 2.3, phastCons 1
Regional constraint	o/e 0.95	unconstrained · MANE · 855 bp · p 0.77 · regional, not allelic
Overall
CADD	25.2	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 8.47e-05% European (non-Finnish) · 1/1,179,970 alleles

Overall 6.2e-05% 1/1,614,082 alleles · very rare exomes 1/1,461,816 · genomes 0/152,266 · joint denominator

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: TOMM22
Protein: p.Leu135Pro
Coding: c.404T>C
MANE Select: NM_020243
dbSNP: rs1429439009
Type: single nucleotide variant
Location: chr22:38683816 (GRCh38)
Gene constraint: LOEUF 0.458 · pLI 0.98 (gnomAD)
Structure: AlphaFold pLDDT 72.65 · 14 PDB
Residue 135: the 'c-tail signal; necessary for mitochondrion outer membrane localization and integration in the tom complex' region

Full TOMM22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TOMM22 p.Ala134Pro Uncertain significance ★ ⚠ same type
TOMM22 p.Arg117Trp Uncertain significance ★ ⚠ same type
TOMM22 p.Gln107His Uncertain significance ★ ⚠ same type
TOMM22 p.Gly133Glu Uncertain significance ★ ⚠ same type
TOMM22 p.Leu127Val Uncertain significance ★ ⚠ same type
TOMM22 p.Lys105Glu Uncertain significance ★ ⚠ same type
TOMM22 p.Pro136Leu 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/tomm22-p-leu135pro (accessed [today's date]).

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