Is INMT p.Pro151Leu (c.452C>T) pathogenic?

INMT p.Pro151Leu (c.452C>T) is classified Uncertain significance in INMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-02-24). AlphaMissense: likely benign (0.2007); Ultra-rare (popmax 0.0445%, eas).

How common is INMT p.Pro151Leu (c.452C>T) in the general population?

INMT p.Pro151Leu (c.452C>T) is ultra-rare (popmax 0.0445%, eas) (gnomAD).

What do computational predictors say about INMT p.Pro151Leu (c.452C>T)?

AlphaMissense predicts likely benign (score 0.2007) — an in-silico prediction, not a clinical call.

INMT p.Pro151Leu

c.452C>T · VCV3860546

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2007 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0445%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2007	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	LLR -11.81	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.72	GERP -3.6
Regional constraint	o/e 0.94	unconstrained · MANE · 3,697 bp · p 0.27 · regional, not allelic
Overall
CADD	15.41	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 0.0445% East Asian · 20/44,896 alleles

Filtering AF 0.0295% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0246%

Overall 0.00386% 62/1,607,548 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0445%	2,245
South Asian	0.0329%	3,036
Remaining individualsnot grpmax-eligible	0.00641%	15,612
Admixed American	0.00333%	30,004
European (non-Finnish)	0.000508%	196,667

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: INMT
Protein: p.Pro151Leu
Coding: c.452C>T
MANE Select: NM_006774
Type: single nucleotide variant
Location: chr7:30755511 (GRCh38)
Gene constraint: LOEUF 1.467 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 97.14 · 1 PDB
Residue 151: a turn

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

Similar variants

INMT c.363-7T>A Likely benign ★★ same type
INMT p.Ala104Thr Uncertain significance ★ ⚠ same type
INMT p.Ala134Glu Uncertain significance ★ ⚠ same type
INMT p.Ala215Thr Uncertain significance ★ ⚠ same type
INMT p.Ala247Ser Uncertain significance ★ ⚠ same type
INMT p.Ala247Val Uncertain significance ★ ⚠ same type
INMT p.Arg137Trp Uncertain significance ★ ⚠ same type
INMT p.Arg177His 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/inmt-p-pro151leu (accessed [today's date]).

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