Is RNF133 p.Pro141Ser (c.421C>T) pathogenic?

RNF133 p.Pro141Ser (c.421C>T) is classified Uncertain significance in RNF133 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-16). AlphaMissense: likely benign (0.2814); Very rare (popmax 0.00892%, eas).

How common is RNF133 p.Pro141Ser (c.421C>T) in the general population?

RNF133 p.Pro141Ser (c.421C>T) is very rare (popmax 0.00892%, eas) (gnomAD).

What do computational predictors say about RNF133 p.Pro141Ser (c.421C>T)?

AlphaMissense predicts likely benign (score 0.2814) — an in-silico prediction, not a clinical call.

RNF133 p.Pro141Ser

c.421C>T · rs552361899 · VCV3155028

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2814 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2814	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -6.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,127 bp · p 0.38 · regional, not allelic
Overall
CADD	22.7	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 0.00892% East Asian · 4/44,864 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.000434% 7/1,613,912 alleles · very rare exomes 4/1,461,714 · genomes 3/152,198 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,216
African / African-American	0.00267%	37,501
Finnishnot grpmax-eligible	0.00156%	64,010

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.Pro141Ser
Coding: c.421C>T
MANE Select: NM_139175
dbSNP: rs552361899
Type: single nucleotide variant
Location: chr7:122698498 (GRCh38)
Gene constraint: LOEUF 1.826 · pLI 0.35 (gnomAD)
Structure: AlphaFold pLDDT 77.48
Residue 141: the pa domain

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

Similar variants

RNF133 p.Ala203Thr Uncertain significance ★ ⚠ same type
RNF133 p.Ala343Thr Uncertain significance ★ ⚠ same type
RNF133 p.Arg107Trp Uncertain significance ★ ⚠ same type
RNF133 p.Arg217Lys Uncertain significance ★ ⚠ same type
RNF133 p.Arg221Gln Uncertain significance ★ ⚠ same type
RNF133 p.Arg225Gln Uncertain significance ★ same type
RNF133 p.Arg270Cys Uncertain significance ★ ⚠ same type
RNF133 p.Asn157Lys 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/rnf133-p-pro141ser (accessed [today's date]).

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