Is RNF4 p.Arg19Gln (c.56G>A) pathogenic?

RNF4 p.Arg19Gln (c.56G>A) is classified Uncertain significance in RNF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-05). AlphaMissense: likely benign (0.0846); Very rare (popmax 0.00195%, nfe).

How common is RNF4 p.Arg19Gln (c.56G>A) in the general population?

RNF4 p.Arg19Gln (c.56G>A) is very rare (popmax 0.00195%, nfe) (gnomAD).

What do computational predictors say about RNF4 p.Arg19Gln (c.56G>A)?

AlphaMissense predicts likely benign (score 0.0846) — an in-silico prediction, not a clinical call.

RNF4 p.Arg19Gln

c.56G>A · VCV4155688

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0846 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00195%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0846	likely benign
REVEL	0.114	moderately benign-leaning
SaProt	LLR -10.71	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 2.2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.28 · regional, not allelic
Overall
CADD	26.4	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 0.00195% European (non-Finnish) · 23/1,177,814 alleles

Filtering AF 0.0013% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00109%

Overall 0.00149% 24/1,608,796 alleles · very rare exomes 23/1,456,840 · genomes 1/151,956 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00195%	51,209
South Asian	0.00111%	89,762

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: RNF4
Protein: p.Arg19Gln
Coding: c.56G>A
MANE Select: NM_002938
Type: single nucleotide variant
Location: chr4:2497053 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.88 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.04 · 3 PDB
Residue 19: the 'disordered' region; the 'mediates interaction with trps1' region

Full RNF4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RNF4 p.Ala16Val Uncertain significance ★ ⚠ same type
RNF4 p.Arg102Lys Uncertain significance ★ ⚠ same type
RNF4 p.Arg147His Uncertain significance ★ ⚠ same type
RNF4 p.Arg164Cys Uncertain significance ★ ⚠ same type
RNF4 p.Arg6Cys Uncertain significance ★ ⚠ same type
RNF4 p.Arg6His Uncertain significance ★ ⚠ same type
RNF4 p.Arg78Lys Uncertain significance ★ ⚠ same type
RNF4 p.Arg78Ser 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/rnf4-p-arg19gln (accessed [today's date]).

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