Is RNF4 p.Arg78Ser (c.234G>T) pathogenic?

RNF4 p.Arg78Ser (c.234G>T) is classified Uncertain significance in RNF4 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: ambiguous (0.4461); Ultra-rare (popmax 0.0495%, mid).

How common is RNF4 p.Arg78Ser (c.234G>T) in the general population?

RNF4 p.Arg78Ser (c.234G>T) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about RNF4 p.Arg78Ser (c.234G>T)?

AlphaMissense predicts ambiguous (score 0.4461) — an in-silico prediction, not a clinical call.

RNF4 p.Arg78Ser

c.234G>T · rs377600326 · VCV2362553

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4461 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4461	ambiguous
REVEL	0.231	benign-leaning
SaProt	LLR -7.42	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -2.5, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 23 kb · p 0.28 · regional, not allelic
Overall
CADD	21.3	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 0.0495% Middle Eastern · 3/6,060 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.00391% 63/1,612,320 alleles · ultra-rare exomes 57/1,460,076 · genomes 6/152,244 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,020
African / African-American	0.0147%	6,817
Remaining individualsnot grpmax-eligible	0.00801%	12,484
South Asian	0.00441%	22,701
Ashkenazi Jewishnot grpmax-eligible	0.00339%	29,542
European (non-Finnish)	0.00322%	31,031
Admixed American	0.00168%	59,672

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.Arg78Ser
Coding: c.234G>T
MANE Select: NM_002938
dbSNP: rs377600326
Type: single nucleotide variant
Location: chr4:2512457 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI 0.88 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 73.04 · 3 PDB

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

Similar variants

RNF4 p.Arg78Lys Uncertain significance ★ ⚠ same residue
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

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-arg78ser (accessed [today's date]).

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