Is RPGRIP1 p.Pro650Arg (c.1949C>G) pathogenic?

RPGRIP1 p.Pro650Arg (c.1949C>G) is classified Uncertain significance in RPGRIP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.7609); Absent from gnomAD v4.1; Associated with cone-rod dystrophy 13.

What condition is associated with RPGRIP1 p.Pro650Arg (c.1949C>G)?

RPGRIP1 p.Pro650Arg (c.1949C>G) is associated with cone-rod dystrophy 13, Leber congenital amaurosis 6 (ClinVar).

How common is RPGRIP1 p.Pro650Arg (c.1949C>G) in the general population?

RPGRIP1 p.Pro650Arg (c.1949C>G) is absent from gnomAD v4.1 (gnomAD).

How is Cone rod dystrophy inherited?

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

What do computational predictors say about RPGRIP1 p.Pro650Arg (c.1949C>G)?

AlphaMissense predicts likely pathogenic (score 0.7609) — an in-silico prediction, not a clinical call.

RPGRIP1 p.Pro650Arg

c.1949C>G · rs769167245 · VCV1374357

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7609 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cone-rod dystrophy 13

Computational evidence

Protein change
AlphaMissense	0.7609	likely pathogenic · top 7% in RPGRIP1
REVEL	0.67	pathogenic-leaning
SaProt	LLR -16.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 0.93, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 63 kb · p 0.13 · regional, not allelic
Overall
CADD	23.9	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: RPGRIP1
Protein: p.Pro650Arg
Coding: c.1949C>G
MANE Select: NM_020366
dbSNP: rs769167245
Type: single nucleotide variant
Location: chr14:21324804 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.60 · 1 PDB

Full RPGRIP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cone-rod dystrophy 13 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Leber congenital amaurosis 6

For Cone rod dystrophy (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Adolescent, Adult, Childhood
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RPGRIP1 p.Pro650Leu Uncertain significance ★ ⚠ same residue
RPGRIP1 p.Pro650Ser Likely pathogenic ★ same residue
RPGRIP1 c.1467+1G>A Pathogenic/Likely pathogenic ★★ same condition
RPGRIP1 c.1468-2A>G Pathogenic/Likely pathogenic ★★ same condition
RPGRIP1 c.218+1G>T Likely pathogenic ★★ same condition
RPGRIP1 c.2367+1G>A Pathogenic ★★ same condition
RPGRIP1 c.2368-2A>G Pathogenic/Likely pathogenic ★★ same condition
RPGRIP1 c.2711-2A>G 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/rpgrip1-p-pro650arg (accessed [today's date]).

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