Is RNPC3 p.Arg464His (c.1391G>A) pathogenic?

RNPC3 p.Arg464His (c.1391G>A) is classified Uncertain significance in RNPC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-06). AlphaMissense: likely pathogenic (0.9887); Ultra-rare (popmax 0.0438%, mid); Associated with Inborn genetic diseases.

What condition is associated with RNPC3 p.Arg464His (c.1391G>A)?

RNPC3 p.Arg464His (c.1391G>A) is associated with Inborn genetic diseases (ClinVar).

How common is RNPC3 p.Arg464His (c.1391G>A) in the general population?

RNPC3 p.Arg464His (c.1391G>A) is ultra-rare (popmax 0.0438%, mid) (gnomAD).

What do computational predictors say about RNPC3 p.Arg464His (c.1391G>A)?

AlphaMissense predicts likely pathogenic (score 0.9887) — an in-silico prediction, not a clinical call.

RNPC3 p.Arg464His

c.1391G>A · VCV4863442

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9887 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0438%, mid)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9887	likely pathogenic · top 9% in RNPC3
REVEL	0.527	indeterminate
SaProt	LLR -13.79	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.9	GERP 0.92, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 5,442 bp · p 0.34 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0438% Middle Eastern · 2/4,568 alleles

Filtering AF 0.00777% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00317%

Overall 0.00149% 24/1,611,034 alleles · ultra-rare exomes 22/1,458,892 · genomes 2/152,142 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0438%	2,284
East Asian	0.00447%	22,396
European (non-Finnish)	0.00161%	62,064
South Asian	0.0011%	90,948

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: RNPC3
Protein: p.Arg464His
Coding: c.1391G>A
MANE Select: NM_017619
Type: single nucleotide variant
Location: chr1:103550970 (GRCh38)
Gene constraint: LOEUF 1.041 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.73 · 2 PDB
Residue 464: the rrm 2 domain; a turn

Full RNPC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RNPC3 p.Ala204Val Uncertain significance ★ ⚠ same condition
RNPC3 p.Arg120Gly Uncertain significance ★ ⚠ same condition
RNPC3 p.Arg205Gln Uncertain significance ★ ⚠ same condition
RNPC3 p.Arg254Gln Uncertain significance ★ ⚠ same condition
RNPC3 p.Arg277Cys Uncertain significance ★ ⚠ same condition
RNPC3 p.Arg452Trp Uncertain significance ★ ⚠ same condition
RNPC3 p.Arg458Leu Uncertain significance ★ ⚠ same condition
RNPC3 p.Asn359Ser Uncertain significance ★ ⚠ same condition

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/rnpc3-p-arg464his (accessed [today's date]).

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