Is RNPC3 p.Pro474Leu (c.1421C>T) pathogenic?

RNPC3 p.Pro474Leu (c.1421C>T) is classified Uncertain significance in RNPC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-04). AlphaMissense: likely pathogenic (0.9536); Absent from gnomAD v4.1; Associated with isolated growth hormone deficiency, type 5.

What condition is associated with RNPC3 p.Pro474Leu (c.1421C>T)?

RNPC3 p.Pro474Leu (c.1421C>T) is associated with isolated growth hormone deficiency, type 5 (ClinVar).

How common is RNPC3 p.Pro474Leu (c.1421C>T) in the general population?

RNPC3 p.Pro474Leu (c.1421C>T) is absent from gnomAD v4.1 (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.

What do computational predictors say about RNPC3 p.Pro474Leu (c.1421C>T)?

AlphaMissense predicts likely pathogenic (score 0.9536) — an in-silico prediction, not a clinical call.

RNPC3 p.Pro474Leu

c.1421C>T · rs2524145667 · VCV3068053

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9536 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

isolated growth hormone deficiency, type 5

Computational evidence

Protein change
AlphaMissense	0.9536	likely pathogenic
REVEL	0.613	indeterminate
SaProt	LLR -13.94	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 7.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 5,442 bp · p 0.34 · regional, not allelic
Overall
CADD	28.9	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: RNPC3
Protein: p.Pro474Leu
Coding: c.1421C>T
MANE Select: NM_017619
dbSNP: rs2524145667
Type: single nucleotide variant
Location: chr1:103551000 (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.Pro474Thr Pathogenic same residue
RNPC3 p.Pro474fs 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.Asn342Thr 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-pro474leu (accessed [today's date]).

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