Is RBM22 p.Ser346Pro (c.1036T>C) pathogenic?

RBM22 p.Ser346Pro (c.1036T>C) is classified Uncertain significance in RBM22 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-14). AlphaMissense: likely benign (0.0975); Very rare (popmax 0.00502%, amr).

How common is RBM22 p.Ser346Pro (c.1036T>C) in the general population?

RBM22 p.Ser346Pro (c.1036T>C) is very rare (popmax 0.00502%, amr) (gnomAD).

What do computational predictors say about RBM22 p.Ser346Pro (c.1036T>C)?

AlphaMissense predicts likely benign (score 0.0975) — an in-silico prediction, not a clinical call.

RBM22 p.Ser346Pro

c.1036T>C · VCV3787524

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0975 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00502%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0975	likely benign
REVEL	0.038	moderately benign-leaning
SaProt	LLR -5.49	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.77	unconstrained · MANE · 1,524 bp · p 0.0078 · regional, not allelic
Overall
CADD	22.0	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 0.00502% Admixed American · 3/59,784 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000669%

Overall 0.000205% 3/1,460,338 alleles · very rare

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: RBM22
Protein: p.Ser346Pro
Coding: c.1036T>C
MANE Select: NM_018047
Type: single nucleotide variant
Location: chr5:150692991 (GRCh38)
Gene constraint: LOEUF 0.092 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 77.10 · 35 PDB

Full RBM22 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RBM22 p.Ala279Thr Uncertain significance ★ ⚠ same type
RBM22 p.Ala345Gly Uncertain significance ★ ⚠ same type
RBM22 p.Ala99Thr Uncertain significance ★ ⚠ same type
RBM22 p.Arg161Gln Uncertain significance ★ ⚠ same type
RBM22 p.Arg216Gln Uncertain significance ★ ⚠ same type
RBM22 p.Arg62His Uncertain significance ★ ⚠ same type
RBM22 p.Asn113Asp Uncertain significance ★ ⚠ same type
RBM22 p.Glu342Ala 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/rbm22-p-ser346pro (accessed [today's date]).

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