Is TOM1 p.Ala401Pro (c.1201G>C) pathogenic?

TOM1 p.Ala401Pro (c.1201G>C) is classified Uncertain significance in TOM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-03). AlphaMissense: ambiguous (0.3721); Very rare (popmax 8.51e-05%, nfe).

How common is TOM1 p.Ala401Pro (c.1201G>C) in the general population?

TOM1 p.Ala401Pro (c.1201G>C) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

What do computational predictors say about TOM1 p.Ala401Pro (c.1201G>C)?

AlphaMissense predicts ambiguous (score 0.3721) — an in-silico prediction, not a clinical call.

TOM1 p.Ala401Pro

c.1201G>C · rs773071776 · VCV2653091

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3721 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3721	ambiguous
REVEL	0.163	moderately benign-leaning
SaProt	LLR -6.24	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 47 kb · p 0.0076 · regional, not allelic
Overall
CADD	24.4	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 8.51e-05% European (non-Finnish) · 1/1,175,028 alleles

Overall 6.25e-05% 1/1,601,252 alleles · very rare exomes 1/1,449,118 · genomes 0/152,134 · 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: TOM1
Protein: p.Ala401Pro
Coding: c.1201G>C
MANE Select: NM_005488
dbSNP: rs773071776
Type: single nucleotide variant
Location: chr22:35338765 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.67 · 6 PDB
Residue 401: the 'interaction with myo6' region

Full TOM1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

TOM1 p.Arg450Gln Uncertain significance ★★ ⚠ same type
TOM1 p.Asp324Asn Uncertain significance ★★ ⚠ same type
TOM1 p.Ile40Val Uncertain significance ★★ ⚠ same type
TOM1 p.Ser461Phe Uncertain significance ★★ ⚠ same type
TOM1 p.Asp38= Benign ★★ same type
TOM1 p.Ser235= Benign ★★ same type
TOM1 c.1028-8C>T Uncertain significance ★ same type
TOM1 c.138-6C>T 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/tom1-p-ala401pro (accessed [today's date]).

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