Is RNF4 p.Ser25Phe (c.74C>T) pathogenic?

RNF4 p.Ser25Phe (c.74C>T) is classified Uncertain significance in RNF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-02). AlphaMissense: likely benign (0.1203); Ultra-rare (popmax 0.0228%, afr).

How common is RNF4 p.Ser25Phe (c.74C>T) in the general population?

RNF4 p.Ser25Phe (c.74C>T) is ultra-rare (popmax 0.0228%, afr) (gnomAD).

What do computational predictors say about RNF4 p.Ser25Phe (c.74C>T)?

AlphaMissense predicts likely benign (score 0.1203) — an in-silico prediction, not a clinical call.

RNF4 p.Ser25Phe

c.74C>T · rs752921900 · VCV2384278

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1203 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0228%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1203	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -8.99	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 3.8	GERP 2.2, phastCons 0.31
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.28 · regional, not allelic
Overall
CADD	17.14	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 0.0228% African / African-American · 17/74,720 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0119%

Overall 0.00124% 20/1,609,568 alleles · ultra-rare exomes 10/1,457,698 · genomes 10/151,870 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0228%	4,395
Admixed American	0.00168%	59,388
Remaining individualsnot grpmax-eligible	0.0016%	62,354
European (non-Finnish)	8.49e-05%	1,178,142

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.Ser25Phe
Coding: c.74C>T
MANE Select: NM_002938
dbSNP: rs752921900
Type: single nucleotide variant
Location: chr4:2497071 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.88 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.04 · 3 PDB
Residue 25: 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.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

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-ser25phe (accessed [today's date]).

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