Is RPRD2 p.Arg366Cys (c.1096C>T) pathogenic?

RPRD2 p.Arg366Cys (c.1096C>T) is classified Uncertain significance in RPRD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-02). AlphaMissense: ambiguous (0.3527); Very rare (popmax 0.000678%, nfe).

How common is RPRD2 p.Arg366Cys (c.1096C>T) in the general population?

RPRD2 p.Arg366Cys (c.1096C>T) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about RPRD2 p.Arg366Cys (c.1096C>T)?

AlphaMissense predicts ambiguous (score 0.3527) — an in-silico prediction, not a clinical call.

RPRD2 p.Arg366Cys

c.1096C>T · VCV3435283

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3527 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3527	ambiguous
REVEL	0.244	benign-leaning
SaProt	LLR -7.53	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.73	unconstrained · MANE · 54 kb · p 1.7e-14 · regional, not allelic
Overall
CADD	27.1	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 0.000678% European (non-Finnish) · 8/1,179,754 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,613,654 alleles · very rare exomes 5/1,461,548 · genomes 3/152,106 · 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: RPRD2
Protein: p.Arg366Cys
Coding: c.1096C>T
MANE Select: NM_015203
Type: single nucleotide variant
Location: chr1:150457513 (GRCh38)
Gene constraint: LOEUF 0.145 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 48.32 · 3 PDB
Residue 366: the 'disordered' region

Full RPRD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

RPRD2 p.Glu195= Benign ★★ same type
RPRD2 p.Ala1083Ser Uncertain significance ★ ⚠ same type
RPRD2 p.Ala1145Pro Uncertain significance ★ ⚠ same type
RPRD2 p.Ala1149Val Uncertain significance ★ ⚠ same type
RPRD2 p.Ala1165Val Uncertain significance ★ ⚠ same type
RPRD2 p.Ala1251Thr Uncertain significance ★ ⚠ same type
RPRD2 p.Ala140Val Uncertain significance ★ ⚠ same type
RPRD2 p.Ala442Pro 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/rprd2-p-arg366cys (accessed [today's date]).

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