Is RPGRIP1 p.Ala960Pro (c.2878G>C) pathogenic?

RPGRIP1 p.Ala960Pro (c.2878G>C) is classified Conflicting classifications of pathogenicity in RPGRIP1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0767); Low-frequency (popmax 1.59%, afr); Associated with Leber congenital amaurosis 6.

What condition is associated with RPGRIP1 p.Ala960Pro (c.2878G>C)?

RPGRIP1 p.Ala960Pro (c.2878G>C) is associated with Leber congenital amaurosis 6, cone-rod dystrophy 13 (ClinVar).

How common is RPGRIP1 p.Ala960Pro (c.2878G>C) in the general population?

RPGRIP1 p.Ala960Pro (c.2878G>C) is low-frequency (popmax 1.59%, afr) (gnomAD).

How is Leber congenital amaurosis 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.Ala960Pro (c.2878G>C)?

AlphaMissense predicts likely benign (score 0.0767) — an in-silico prediction, not a clinical call.

RPGRIP1 p.Ala960Pro

c.2878G>C · rs35810926 · VCV534365

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0767 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.59%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Leber congenital amaurosis 6

Computational evidence

Protein change
AlphaMissense	0.0767	likely benign
REVEL	0.111	moderately benign-leaning
SaProt	LLR -5.91	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 -5.3	GERP -3.1
Regional constraint	o/e 0.96	unconstrained · MANE · 63 kb · p 0.13 · regional, not allelic
Overall
CADD	0.029	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 1.59% African / African-American · 1,180/74,308 alleles

Filtering AF 1.51% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.48%

Overall 0.0898% 1,434/1,597,138 alleles · low-frequency exomes 767/1,444,834 · genomes 667/152,304 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.59%	63
Admixed American	0.118%	846
Remaining individualsnot grpmax-eligible	0.109%	920
Middle Eastern	0.0336%	2,979
East Asian	0.0246%	4,064
European (non-Finnish)	0.00862%	11,601
South Asian	0.00675%	14,808

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.Ala960Pro
Coding: c.2878G>C
MANE Select: NM_020366
dbSNP: rs35810926
Type: single nucleotide variant
Location: chr14:21327790 (GRCh38)
Gene constraint: LOEUF 0.918 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 67.60 · 1 PDB
Residue 960: the 'disordered' region; a UniProt-annotated variant site (in)

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

Disease context

Leber congenital amaurosis 6 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cone-rod dystrophy 13

For Leber congenital amaurosis (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Infancy, Neonatal
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

RPGRIP1 p.Ala960Ser Uncertain significance ★★ ⚠ same residue
RPGRIP1 p.Ala960Thr Uncertain significance ★★ ⚠ 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-ala960pro (accessed [today's date]).

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