Is RNPC3 p.Pro474Thr (c.1420C>A) pathogenic?

RNPC3 p.Pro474Thr (c.1420C>A) is classified Pathogenic in RNPC3 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2021-11-05). AlphaMissense: likely pathogenic (0.9381); Very rare (popmax 0.00134%, afr); Associated with isolated growth hormone deficiency, type 5.

What condition is associated with RNPC3 p.Pro474Thr (c.1420C>A)?

RNPC3 p.Pro474Thr (c.1420C>A) is associated with isolated growth hormone deficiency, type 5 (ClinVar).

How common is RNPC3 p.Pro474Thr (c.1420C>A) in the general population?

RNPC3 p.Pro474Thr (c.1420C>A) is very rare (popmax 0.00134%, afr) (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.Pro474Thr (c.1420C>A)?

AlphaMissense predicts likely pathogenic (score 0.9381) — an in-silico prediction, not a clinical call.

RNPC3 p.Pro474Thr

c.1420C>A · rs370930012 · VCV587367

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9381 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

isolated growth hormone deficiency, type 5

Computational evidence

Protein change
AlphaMissense	0.9381	likely pathogenic ✓ concordant with ClinVar
REVEL	0.779	moderately pathogenic-leaning
SaProt	LLR -12.40	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	27.4	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 0.00134% African / African-American · 1/74,840 alleles

Filtering AF 0.000689% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.000993% 16/1,611,368 alleles · very rare exomes 12/1,459,260 · genomes 4/152,108 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,840
European (non-Finnish)	0.00119%	84,222
South Asian	0.0011%	90,970

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.Pro474Thr
Coding: c.1420C>A
MANE Select: NM_017619
dbSNP: rs370930012
Type: single nucleotide variant
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.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-pro474thr (accessed [today's date]).

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