Is CEP250 p.Arg1992Cys (c.5974C>T) pathogenic?

CEP250 p.Arg1992Cys (c.5974C>T) is classified Likely benign in CEP250 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.0917); Rare (popmax 0.398%, mid).

How common is CEP250 p.Arg1992Cys (c.5974C>T) in the general population?

CEP250 p.Arg1992Cys (c.5974C>T) is rare (popmax 0.398%, mid) (gnomAD).

What do computational predictors say about CEP250 p.Arg1992Cys (c.5974C>T)?

AlphaMissense predicts likely benign (score 0.0917) — an in-silico prediction, not a clinical call.

CEP250 p.Arg1992Cys

c.5974C>T · rs41290926 · VCV730752

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0917 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.398%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0917	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -9.51	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 0.14	GERP -1.1, phastCons 0.003
Regional constraint	o/e 0.87	unconstrained · MANE · 49 kb · p 4.8e-12 · regional, not allelic
Overall
CADD	12.87	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 0.398% Middle Eastern · 24/6,026 alleles

Filtering AF 0.329% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.326%

Overall 0.311% 4,951/1,593,702 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.398%	251
Finnishnot grpmax-eligible	0.396%	252
Ashkenazi Jewishnot grpmax-eligible	0.388%	258
European (non-Finnish)	0.338%	296
South Asian	0.281%	356
Remaining individualsnot grpmax-eligible	0.257%	388
Admixed American	0.232%	432
African / African-American	0.0778%	1,286
East Asian	0.0252%	3,972

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.Arg1992Cys
Coding: c.5974C>T
MANE Select: NM_007186
dbSNP: rs41290926
Type: single nucleotide variant
Location: chr20:35504343 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 1 PDB
Residue 1992: 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.Arg1992His Uncertain significance ★★ ⚠ same residue
CEP250 p.Arg1992Leu 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

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-arg1992cys (accessed [today's date]).

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