Is RPGRIP1 p.Pro650Ser (c.1948C>T) pathogenic?

RPGRIP1 p.Pro650Ser (c.1948C>T) is classified Likely pathogenic in RPGRIP1 (ClinVar, Single submitter, 3 submitters; last evaluated 2019-01-01). AlphaMissense: likely pathogenic (0.7163); Very rare (popmax 0.000254%, nfe); Associated with inherited retinal dystrophy.

What condition is associated with RPGRIP1 p.Pro650Ser (c.1948C>T)?

RPGRIP1 p.Pro650Ser (c.1948C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is RPGRIP1 p.Pro650Ser (c.1948C>T) in the general population?

RPGRIP1 p.Pro650Ser (c.1948C>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about RPGRIP1 p.Pro650Ser (c.1948C>T)?

AlphaMissense predicts likely pathogenic (score 0.7163) — an in-silico prediction, not a clinical call.

RPGRIP1 p.Pro650Ser

c.1948C>T · rs1740380459 · VCV1284419

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.7163	likely pathogenic ✓ concordant with ClinVar · top 8% in RPGRIP1
REVEL	0.577	indeterminate
SaProt	LLR -13.57	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 63 kb · p 0.13 · regional, not allelic
Overall
CADD	24.7	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 0.000254% European (non-Finnish) · 3/1,179,900 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000186% 3/1,614,066 alleles · very rare exomes 3/1,461,708 · genomes 0/152,358 · 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: RPGRIP1
Protein: p.Pro650Ser
Coding: c.1948C>T
MANE Select: NM_020366
dbSNP: rs1740380459
Type: single nucleotide variant
Location: chr14:21324803 (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

inherited retinal dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

RPGRIP1 p.Pro650Arg Uncertain significance ★★ ⚠ same residue
RPGRIP1 p.Pro650Leu Uncertain significance ★ ⚠ same residue
RPGRIP1 c.800+1G>A Pathogenic/Likely pathogenic ★★ same condition
RPGRIP1 p.Arg852Ter Pathogenic ★★ same condition
RPGRIP1 p.Gln772Ter Pathogenic ★★ same condition
RPGRIP1 p.Lys435Ter Pathogenic ★★ same condition
RPGRIP1 p.Pro674His Likely pathogenic ★★ same condition
RPGRIP1 p.Ala837Gly 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/rpgrip1-p-pro650ser (accessed [today's date]).

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