Is RNF4 p.Ala16Val (c.47C>T) pathogenic?

RNF4 p.Ala16Val (c.47C>T) is classified Uncertain significance in RNF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-14). AlphaMissense: likely benign (0.0949); Very rare (popmax 0.00508%, amr).

How common is RNF4 p.Ala16Val (c.47C>T) in the general population?

RNF4 p.Ala16Val (c.47C>T) is very rare (popmax 0.00508%, amr) (gnomAD).

What do computational predictors say about RNF4 p.Ala16Val (c.47C>T)?

AlphaMissense predicts likely benign (score 0.0949) — an in-silico prediction, not a clinical call.

RNF4 p.Ala16Val

c.47C>T · rs753448501 · VCV2237295

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0949 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00508%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0949	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -6.19	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 2.7	GERP 2.2, phastCons 0.27
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.28 · regional, not allelic
Overall
CADD	21.9	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 0.00508% Admixed American · 3/59,108 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000673%

Overall 0.000249% 4/1,607,920 alleles · very rare exomes 4/1,455,880 · genomes 0/152,040 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00508%	19,703
European (non-Finnish)	8.49e-05%	1,177,296

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.Ala16Val
Coding: c.47C>T
MANE Select: NM_002938
dbSNP: rs753448501
Type: single nucleotide variant
Location: chr4:2497044 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.88 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.04 · 3 PDB
Residue 16: the 'disordered' region; the 'required for ubiquitination activity' 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.Arg102Lys Uncertain significance ★ ⚠ same type
RNF4 p.Arg147His Uncertain significance ★ ⚠ same type
RNF4 p.Arg164Cys Uncertain significance ★ ⚠ same type
RNF4 p.Arg19Gln 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-ala16val (accessed [today's date]).

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