Is CEP250 p.Arg595Trp (c.1783C>T) pathogenic?

CEP250 p.Arg595Trp (c.1783C>T) is classified Uncertain significance in CEP250 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-11-25). AlphaMissense: likely benign (0.1738); Ultra-rare (popmax 0.0266%, nfe).

How common is CEP250 p.Arg595Trp (c.1783C>T) in the general population?

CEP250 p.Arg595Trp (c.1783C>T) is ultra-rare (popmax 0.0266%, nfe) (gnomAD).

What do computational predictors say about CEP250 p.Arg595Trp (c.1783C>T)?

AlphaMissense predicts likely benign (score 0.1738) — an in-silico prediction, not a clinical call.

CEP250 p.Arg595Trp

c.1783C>T · rs201227843 · VCV1053295

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1738 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0266%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1738	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -11.05	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 49 kb · p 4.8e-12 · regional, not allelic
Overall
CADD	28.8	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 0.0266% European (non-Finnish) · 314/1,179,962 alleles

Filtering AF 0.0242% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0232%

Overall 0.0201% 324/1,613,988 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0266%	3,758
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Admixed American	0.00167%	59,994
African / African-American	0.00133%	74,918
South Asian	0.0011%	91,092

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.Arg595Trp
Coding: c.1783C>T
MANE Select: NM_007186
dbSNP: rs201227843
Type: single nucleotide variant
Location: chr20:35476515 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 1 PDB
Residue 595: a UniProt-annotated variant site (in crdhl2); a UniProt-annotated variant site (in crdhl2; also found in a family with non-syndromic retinitis pigmentosa)

Full CEP250 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CEP250 p.Arg595Gln Uncertain significance ★ ⚠ same residue
CEP250 p.Arg1045Ter Pathogenic/Likely pathogenic ★★ same type
CEP250 p.Arg1155Ter Pathogenic/Likely pathogenic ★★ same type
CEP250 p.Arg1336Ter Pathogenic/Likely pathogenic ★★ same type
CEP250 p.Arg1343Ter Pathogenic/Likely pathogenic ★★ same type
CEP250 p.Arg1499Ter Pathogenic/Likely pathogenic ★★ same type
CEP250 p.Arg1695Ter Pathogenic/Likely pathogenic ★★ same type
CEP250 p.Arg1869Ter Pathogenic/Likely 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-arg595trp (accessed [today's date]).

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