Is RPGRIP1 p.Ser64Phe (c.191C>T) pathogenic?

RPGRIP1 p.Ser64Phe (c.191C>T) is classified Uncertain significance in RPGRIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-09-19). AlphaMissense: likely benign (0.1065); Very rare (popmax 8.66e-05%, nfe); Associated with cone-rod dystrophy 13.

What condition is associated with RPGRIP1 p.Ser64Phe (c.191C>T)?

RPGRIP1 p.Ser64Phe (c.191C>T) is associated with cone-rod dystrophy 13 (ClinVar).

How common is RPGRIP1 p.Ser64Phe (c.191C>T) in the general population?

RPGRIP1 p.Ser64Phe (c.191C>T) is very rare (popmax 8.66e-05%, nfe) (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.Ser64Phe (c.191C>T)?

AlphaMissense predicts likely benign (score 0.1065) — an in-silico prediction, not a clinical call.

RPGRIP1 p.Ser64Phe

c.191C>T · rs1880692860 · VCV1030704

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1065 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.66e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cone-rod dystrophy 13

Computational evidence

Protein change
AlphaMissense	0.1065	likely benign
REVEL	0.147	moderately benign-leaning
SaProt	LLR -7.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.55	GERP -1.4, phastCons 0.82
Regional constraint	o/e 0.96	unconstrained · MANE · 63 kb · p 0.13 · regional, not allelic
Overall
CADD	15.38	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 8.66e-05% European (non-Finnish) · 1/1,154,846 alleles

Overall 6.38e-05% 1/1,566,864 alleles · very rare exomes 1/1,423,184 · genomes 0/143,680 · 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.Ser64Phe
Coding: c.191C>T
MANE Select: NM_020366
dbSNP: rs1880692860
Type: single nucleotide variant
Location: chr14:21294782 (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

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 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
RPGRIP1 c.2895+1G>T Pathogenic ★★ same condition
RPGRIP1 c.3617+1G>A 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-ser64phe (accessed [today's date]).

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