Is CEP250 p.Arg1697Trp (c.5089C>T) pathogenic?

CEP250 p.Arg1697Trp (c.5089C>T) is classified Uncertain significance in CEP250 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-10-17). AlphaMissense: likely benign (0.1072); Ultra-rare (popmax 0.029%, eas); Associated with inherited retinal dystrophy.

What condition is associated with CEP250 p.Arg1697Trp (c.5089C>T)?

CEP250 p.Arg1697Trp (c.5089C>T) is associated with inherited retinal dystrophy (ClinVar).

How common is CEP250 p.Arg1697Trp (c.5089C>T) in the general population?

CEP250 p.Arg1697Trp (c.5089C>T) is ultra-rare (popmax 0.029%, eas) (gnomAD).

What do computational predictors say about CEP250 p.Arg1697Trp (c.5089C>T)?

AlphaMissense predicts likely benign (score 0.1072) — an in-silico prediction, not a clinical call.

CEP250 p.Arg1697Trp

c.5089C>T · rs200384192 · VCV1021023

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1072 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.029%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

inherited retinal dystrophy

Computational evidence

Protein change
AlphaMissense	0.1072	likely benign
REVEL	0.07	moderately benign-leaning
SaProt	LLR -8.80	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 2.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 49 kb · p 4.8e-12 · regional, not allelic
Overall
CADD	21.6	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 0.029% East Asian · 13/44,870 alleles

Filtering AF 0.0171% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.00347% 56/1,613,996 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.029%	3,452
European (non-Finnish)	0.00339%	29,500
Remaining individualsnot grpmax-eligible	0.0016%	62,504
African / African-American	0.00133%	74,960
South Asian	0.0011%	91,074

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: CEP250
Protein: p.Arg1697Trp
Coding: c.5089C>T
MANE Select: NM_007186
dbSNP: rs200384192
Type: single nucleotide variant
Location: chr20:35503458 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 1 PDB
Residue 1697: a UniProt-annotated variant site (in crdhl2); a UniProt-annotated variant site (in crdhl2; also found in a family with non-syndromic retinitis pigmentosa); a UniProt-annotated variant site (in crdhl2; the retinal involvement is more severe in double homozygotes also carrying a pcare truncating variant)

Full CEP250 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

CEP250 p.Arg1697Gln Uncertain significance ★★ ⚠ same residue
CEP250 p.Arg1697Pro Uncertain significance ★★ ⚠ same residue
CEP250 p.Arg1697= Likely benign ★★ same residue
CEP250 p.Ala1988Val Uncertain significance ★★ ⚠ same condition
CEP250 p.Arg1992His Uncertain significance ★★ ⚠ same condition
CEP250 p.Arg519Trp Uncertain significance ★★ ⚠ same condition
CEP250 p.Arg632Gly Uncertain significance ★★ ⚠ same condition
CEP250 p.Leu2178Phe 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/cep250-p-arg1697trp (accessed [today's date]).

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