Is RNF31 p.Arg464Cys (c.1390C>T) pathogenic?

RNF31 p.Arg464Cys (c.1390C>T) is classified Conflicting classifications of pathogenicity in RNF31 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-08). AlphaMissense: likely benign (0.0721); Ultra-rare (popmax 0.0133%, nfe).

How common is RNF31 p.Arg464Cys (c.1390C>T) in the general population?

RNF31 p.Arg464Cys (c.1390C>T) is ultra-rare (popmax 0.0133%, nfe) (gnomAD).

What do computational predictors say about RNF31 p.Arg464Cys (c.1390C>T)?

AlphaMissense predicts likely benign (score 0.0721) — an in-silico prediction, not a clinical call.

RNF31 p.Arg464Cys

c.1390C>T · rs187811103 · VCV1369317

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0721 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0721	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -7.50	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 -1.3	GERP -5.3
Regional constraint	o/e 0.90	unconstrained · MANE · 4,105 bp · p 0.0049 · regional, not allelic
Overall
CADD	9.826	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 0.0133% European (non-Finnish) · 157/1,176,616 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.011%

Overall 0.0109% 176/1,608,972 alleles · ultra-rare exomes 163/1,457,124 · genomes 13/151,848 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0133%	7,494
Finnishnot grpmax-eligible	0.00784%	12,763
Remaining individualsnot grpmax-eligible	0.00642%	15,576
South Asian	0.00552%	18,128
African / African-American	0.00401%	24,930
Admixed American	0.00335%	29,893

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: RNF31
Protein: p.Arg464Cys
Coding: c.1390C>T
MANE Select: NM_017999
dbSNP: rs187811103
Type: single nucleotide variant
Location: chr14:24150790 (GRCh38)
Gene constraint: LOEUF 0.37 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.39 · 36 PDB
Residue 464: the 'disordered' region; the 'polyubiquitin-binding' region

Full RNF31 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RNF31 p.Arg464His Uncertain significance ★ ⚠ same residue
RNF31 p.Ala251Val Uncertain significance ★★ ⚠ same type
RNF31 p.Ala350Gly Uncertain significance ★★ ⚠ same type
RNF31 p.Ala45Val Uncertain significance ★★ ⚠ same type
RNF31 p.Ala501Thr Uncertain significance ★★ ⚠ same type
RNF31 p.Ala503Ser Uncertain significance ★★ ⚠ same type
RNF31 p.Ala503Thr Uncertain significance ★★ ⚠ same type
RNF31 p.Ala539Val 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/rnf31-p-arg464cys (accessed [today's date]).

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