Is RNF133 p.Ser45Leu (c.134C>T) pathogenic?

RNF133 p.Ser45Leu (c.134C>T) is classified Uncertain significance in RNF133 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-15). AlphaMissense: likely benign (0.3127); Very rare (popmax 0.00271%, nfe).

How common is RNF133 p.Ser45Leu (c.134C>T) in the general population?

RNF133 p.Ser45Leu (c.134C>T) is very rare (popmax 0.00271%, nfe) (gnomAD).

What do computational predictors say about RNF133 p.Ser45Leu (c.134C>T)?

AlphaMissense predicts likely benign (score 0.3127) — an in-silico prediction, not a clinical call.

RNF133 p.Ser45Leu

c.134C>T · rs776323822 · VCV2485415

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3127 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00271%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3127	likely benign
REVEL	0.152	moderately benign-leaning
SaProt	LLR -12.53	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,127 bp · p 0.38 · regional, not allelic
Overall
CADD	24.3	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 0.00271% European (non-Finnish) · 32/1,179,846 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00204% 33/1,613,780 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00271%	36,870
South Asian	0.0011%	91,084

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: RNF133
Protein: p.Ser45Leu
Coding: c.134C>T
MANE Select: NM_017954 · reported on NM_139175
dbSNP: rs776323822
Type: single nucleotide variant
Location: chr7:122698785 (GRCh38)

Full RNF133 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

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/rnf133-p-ser45leu (accessed [today's date]).

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