Is RPGRIP1 p.Leu725Val (c.2173C>G) pathogenic?

RPGRIP1 p.Leu725Val (c.2173C>G) is classified Uncertain significance in RPGRIP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-04-16). AlphaMissense: likely benign (0.1413); Very rare (popmax 0.00246%, nfe).

How common is RPGRIP1 p.Leu725Val (c.2173C>G) in the general population?

RPGRIP1 p.Leu725Val (c.2173C>G) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about RPGRIP1 p.Leu725Val (c.2173C>G)?

AlphaMissense predicts likely benign (score 0.1413) — an in-silico prediction, not a clinical call.

RPGRIP1 p.Leu725Val

c.2173C>G · rs755791291 · VCV596730

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1413 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1413	likely benign
REVEL	0.532	indeterminate
SaProt	LLR -10.31	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 63 kb · p 0.13 · regional, not allelic
Overall
CADD	23.3	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 0.00246% European (non-Finnish) · 29/1,179,366 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.0018% 29/1,613,238 alleles · very rare exomes 28/1,461,020 · genomes 1/152,218 · 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.Leu725Val
Coding: c.2173C>G
MANE Select: NM_020366
dbSNP: rs755791291
Type: single nucleotide variant
Location: chr14:21325028 (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

Similar variants

RPGRIP1 c.1467+1G>A Pathogenic/Likely pathogenic ★★ same type
RPGRIP1 c.1468-2A>G Pathogenic/Likely pathogenic ★★ same type
RPGRIP1 c.218+1G>T Likely pathogenic ★★ same type
RPGRIP1 c.2367+1G>A Pathogenic ★★ same type
RPGRIP1 c.2368-2A>G Pathogenic/Likely pathogenic ★★ same type
RPGRIP1 c.2711-2A>G Pathogenic ★★ same type
RPGRIP1 c.2895+1G>T Pathogenic ★★ same type
RPGRIP1 c.3617+1G>A Pathogenic ★★ 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/rpgrip1-p-leu725val (accessed [today's date]).

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