Is RNF31 p.Arg1069Leu (c.3206G>T) pathogenic?

RNF31 p.Arg1069Leu (c.3206G>T) is classified Uncertain significance in RNF31 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.759); Very rare (popmax 0.00414%, afr).

How common is RNF31 p.Arg1069Leu (c.3206G>T) in the general population?

RNF31 p.Arg1069Leu (c.3206G>T) is very rare (popmax 0.00414%, afr) (gnomAD).

What do computational predictors say about RNF31 p.Arg1069Leu (c.3206G>T)?

AlphaMissense predicts likely pathogenic (score 0.759) — an in-silico prediction, not a clinical call.

RNF31 p.Arg1069Leu

c.3206G>T · rs780060640 · VCV1478547

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.759 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00414%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.759	likely pathogenic
REVEL	0.248	benign-leaning
SaProt	LLR -2.71	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 2,629 bp · p 0.079 · regional, not allelic
Overall
CADD	28.3	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 0.00414% African / African-American · 3/72,450 alleles

Filtering AF 0.0011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000505%

Overall 0.000261% 4/1,535,074 alleles · very rare exomes 1/1,382,954 · genomes 3/152,120 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00414%	24,150
European (non-Finnish)	8.78e-05%	1,138,500

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.Arg1069Leu
Coding: c.3206G>T
MANE Select: NM_017999
dbSNP: rs780060640
Type: single nucleotide variant
Location: chr14:24160560 (GRCh38)
Gene constraint: LOEUF 0.37 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 78.39 · 36 PDB
Residue 1069: the 'ldd domain' region

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

Similar variants

RNF31 p.Arg1069Cys 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-arg1069leu (accessed [today's date]).

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