Is RNMT p.Phe322Leu (c.964T>C) pathogenic?

RNMT p.Phe322Leu (c.964T>C) is classified Uncertain significance in RNMT (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-22). AlphaMissense: likely pathogenic (0.6902); Very rare (popmax 0.00515%, amr).

How common is RNMT p.Phe322Leu (c.964T>C) in the general population?

RNMT p.Phe322Leu (c.964T>C) is very rare (popmax 0.00515%, amr) (gnomAD).

What do computational predictors say about RNMT p.Phe322Leu (c.964T>C)?

AlphaMissense predicts likely pathogenic (score 0.6902) — an in-silico prediction, not a clinical call.

RNMT p.Phe322Leu

c.964T>C · rs934008833 · VCV2284885

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6902 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00515%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6902	likely pathogenic
REVEL	0.235	benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.3, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 28 kb · p 0.16 · regional, not allelic
Overall
CADD	26.5	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 0.00515% Admixed American · 3/58,240 alleles

Filtering AF 0.00137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000679%

Overall 0.00025% 4/1,599,872 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00515%	19,413
Remaining individualsnot grpmax-eligible	0.00161%	61,936

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: RNMT
Protein: p.Phe322Leu
Coding: c.964T>C
MANE Select: NM_003799
dbSNP: rs934008833
Type: single nucleotide variant
Location: chr18:13741681 (GRCh38)
Gene constraint: LOEUF 0.92 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.27 · 8 PDB
Residue 322: the mrna cap 0 methyltransferase domain; an α-helix

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

Similar variants

RNMT p.Tyr399= Benign ★★ same type
RNMT p.Ala151Val Uncertain significance ★ ⚠ same type
RNMT p.Ala2Thr Uncertain significance ★ ⚠ same type
RNMT p.Ala56Thr Uncertain significance ★ ⚠ same type
RNMT p.Arg107Gly Uncertain significance ★ ⚠ same type
RNMT p.Arg239Trp Uncertain significance ★ ⚠ same type
RNMT p.Arg247Cys Uncertain significance ★ ⚠ same type
RNMT p.Asn31Thr 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/rnmt-p-phe322leu (accessed [today's date]).

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