Is RNASEL p.Phe420Ile (c.1258T>A) pathogenic?

RNASEL p.Phe420Ile (c.1258T>A) is classified Uncertain significance in RNASEL (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-13). AlphaMissense: likely benign (0.2272); Absent from gnomAD v4.1.

How common is RNASEL p.Phe420Ile (c.1258T>A) in the general population?

RNASEL p.Phe420Ile (c.1258T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about RNASEL p.Phe420Ile (c.1258T>A)?

AlphaMissense predicts likely benign (score 0.2272) — an in-silico prediction, not a clinical call.

RNASEL p.Phe420Ile

c.1258T>A · VCV4155026

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2272 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2272	likely benign
REVEL	0.125	moderately benign-leaning
SaProt	LLR -10.05	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 1.4	GERP -4, phastCons 0.11
Regional constraint	o/e 0.96	unconstrained · MANE · 11 kb · p 0.25 · regional, not allelic
Overall
CADD	17.56	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RNASEL
Protein: p.Phe420Ile
Coding: c.1258T>A
MANE Select: NM_021133
Type: single nucleotide variant
Location: chr1:182585549 (GRCh38)
Gene constraint: LOEUF 0.83 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.96 · 5 PDB
Residue 420: the protein kinase domain; a UniProt-annotated variant site (found in a patient with multisystem inflammatory syndrome; uncertain significance); a β-strand

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

Similar variants

RNASEL p.Phe420= Uncertain significance same residue
RNASEL p.Phe420fs Uncertain significance same residue
RNASEL p.Ile74Thr Uncertain significance ★★ ⚠ same type
RNASEL p.Asn414= Benign ★★ same type
RNASEL p.Gly59Ser Likely benign ★★ ⚠ same type
RNASEL p.Ile97Leu Benign/Likely benign ★★ same type
RNASEL p.Ser113= Benign ★★ same type
RNASEL p.Thr393= Benign/Likely benign ★★ 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/rnasel-p-phe420ile (accessed [today's date]).

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