Is RNPC3 p.Pro474fs (c.1421del) pathogenic?

RNPC3 p.Pro474fs (c.1421del) is classified Pathogenic in RNPC3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-04-05). Very rare (popmax 8.48e-05%, nfe); Associated with isolated growth hormone deficiency, type 5.

What condition is associated with RNPC3 p.Pro474fs (c.1421del)?

RNPC3 p.Pro474fs (c.1421del) is associated with isolated growth hormone deficiency, type 5 (ClinVar).

How common is RNPC3 p.Pro474fs (c.1421del) in the general population?

RNPC3 p.Pro474fs (c.1421del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Non-acquired isolated growth hormone deficiency inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

RNPC3 p.Pro474fs

c.1421del · rs1461692571 · VCV1064671

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

isolated growth hormone deficiency, type 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.2	GERP -1.1, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,136 alleles

Overall 6.2e-05% 1/1,611,606 alleles · very rare exomes 1/1,459,284 · genomes 0/152,322 · joint denominator

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.Pro474fs
Coding: c.1421del
MANE Select: NM_017619
dbSNP: rs1461692571
Type: Deletion
Location: chr1:103550999 (GRCh38)
Gene constraint: LOEUF 1.041 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.73 · 2 PDB
Residue 474: a UniProt-annotated variant site (in cphd7; impairs binding to u12 and u6atac small nuclear rnas; leads to a partial defect in the folding of rrm 2 domain and reduced stability of the full-length protein); the rrm 2 domain

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

Disease context

isolated growth hormone deficiency, type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-acquired isolated growth hormone deficiency (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Neonatal
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

RNPC3 p.Pro474Leu Uncertain significance ★ ⚠ same residue
RNPC3 p.Pro474Thr Pathogenic same residue
RNPC3 c.894-2A>G Likely pathogenic ★★ same condition
RNPC3 p.Asn342His Uncertain significance ★★ ⚠ same condition
RNPC3 c.359+16A>G Benign ★★ same condition
RNPC3 p.Gly114= Benign ★★ same condition
RNPC3 p.Arg205Ter Pathogenic ★ same condition
RNPC3 p.Asn347fs Likely pathogenic ★ 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-pro474fs (accessed [today's date]).

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