Is TOM1 p.Ser461Phe (c.1382C>T) pathogenic?

TOM1 p.Ser461Phe (c.1382C>T) is classified Uncertain significance in TOM1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-20). AlphaMissense: likely benign (0.1212); Rare (popmax 0.181%, mid); Associated with immunodeficiency 85 and autoimmunity.

What condition is associated with TOM1 p.Ser461Phe (c.1382C>T)?

TOM1 p.Ser461Phe (c.1382C>T) is associated with immunodeficiency 85 and autoimmunity (ClinVar).

How common is TOM1 p.Ser461Phe (c.1382C>T) in the general population?

TOM1 p.Ser461Phe (c.1382C>T) is rare (popmax 0.181%, mid) (gnomAD).

What do computational predictors say about TOM1 p.Ser461Phe (c.1382C>T)?

AlphaMissense predicts likely benign (score 0.1212) — an in-silico prediction, not a clinical call.

TOM1 p.Ser461Phe

c.1382C>T · rs144721465 · VCV2341376

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1212 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.181%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 85 and autoimmunity

Computational evidence

Protein change
AlphaMissense	0.1212	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -9.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.3	GERP 1.6, phastCons 0.29
Regional constraint	o/e 0.90	unconstrained · MANE · 47 kb · p 0.0076 · regional, not allelic
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.181% Middle Eastern · 11/6,076 alleles

Filtering AF 0.102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0784%

Overall 0.03% 484/1,613,636 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.181%	552
European (non-Finnish)	0.0359%	2,783
Remaining individualsnot grpmax-eligible	0.0272%	3,675
South Asian	0.0198%	5,060
Admixed American	0.01%	9,990
African / African-American	0.00801%	12,487
East Asian	0.00223%	44,874
Finnishnot grpmax-eligible	0.00156%	63,922

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.Ser461Phe
Coding: c.1382C>T
MANE Select: NM_005488
dbSNP: rs144721465
Type: single nucleotide variant
Location: chr22:35347112 (GRCh38)
Gene constraint: LOEUF 0.866 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.67 · 6 PDB
Residue 461: a modified residue (phosphoserine); the 'interaction with myo6' region; the 'disordered' region

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

Disease context

immunodeficiency 85 and autoimmunity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TOM1 p.Asp324Asn Uncertain significance ★★ ⚠ same condition
TOM1 p.Ile40Val Uncertain significance ★★ ⚠ same condition
TOM1 c.1028-8C>T Uncertain significance ★ same condition
TOM1 p.Gln422Leu Uncertain significance ★ ⚠ same condition
TOM1 p.Gly307Asp Pathogenic ⚠ same condition
TOM1 p.Pro472_Ser473insGlyProPro Uncertain significance ★ same condition
TOM1 p.Ala401Pro Uncertain significance ★★ ⚠ same type
TOM1 p.Arg450Gln 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-ser461phe (accessed [today's date]).

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