Is CEP250 p.Arg1703fs (c.5105dup) pathogenic?

CEP250 p.Arg1703fs (c.5105dup) is classified Pathogenic in CEP250 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-16). Very rare (popmax 0.00267%, afr).

How common is CEP250 p.Arg1703fs (c.5105dup) in the general population?

CEP250 p.Arg1703fs (c.5105dup) is very rare (popmax 0.00267%, afr) (gnomAD).

CEP250 p.Arg1703fs

c.5105dup · rs1303416855 · VCV2098837

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 30 of 35
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 5.7	GERP 0.92, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,906 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000248% 4/1,614,014 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,453
European (non-Finnish)	0.000169%	590,016

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.Arg1703fs
Coding: c.5105dup
MANE Select: NM_007186
dbSNP: rs1303416855
Type: Duplication
Location: chr20:35503473 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 1 PDB
Residue 1703: the 'disordered' region; 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

Similar variants

CEP250 p.Arg1703Trp Uncertain significance ★★ ⚠ same residue
CEP250 p.Glu1795fs Pathogenic ★★ same type
CEP250 c.2755-14dup Benign/Likely benign ★★ same type
CEP250 p.Ala32fs Pathogenic ★ same type
CEP250 p.Ala706fs Likely pathogenic ★ same type
CEP250 p.Arg200fs Pathogenic ★ same type
CEP250 p.Asn856fs Pathogenic ★ same type
CEP250 p.Gln1090fs 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/cep250-p-arg1703fs (accessed [today's date]).

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