Is CEP250 p.Ser1237Phe (c.3710C>T) pathogenic?

CEP250 p.Ser1237Phe (c.3710C>T) is classified Uncertain significance in CEP250 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-25). AlphaMissense: ambiguous (0.4362); Very rare (popmax 0.00134%, afr).

How common is CEP250 p.Ser1237Phe (c.3710C>T) in the general population?

CEP250 p.Ser1237Phe (c.3710C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about CEP250 p.Ser1237Phe (c.3710C>T)?

AlphaMissense predicts ambiguous (score 0.4362) — an in-silico prediction, not a clinical call.

CEP250 p.Ser1237Phe

c.3710C>T · rs1025005664 · VCV2105572

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4362 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4362	ambiguous · top 10% in CEP250
REVEL	0.101	moderately benign-leaning
SaProt	LLR -9.70	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 49 kb · p 4.8e-12 · regional, not allelic
Overall
CADD	23.4	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 0.00134% African / African-American · 1/74,402 alleles

Overall 0.00131% 2/152,178 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,402
European (non-Finnish)	8.49e-05%	1,178,534

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.Ser1237Phe
Coding: c.3710C>T
MANE Select: NM_007186
dbSNP: rs1025005664
Type: single nucleotide variant
Location: chr20:35498649 (GRCh38)
Gene constraint: LOEUF 0.86 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.68 · 1 PDB
Residue 1237: 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.Ser1237= Likely benign ★★ 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-ser1237phe (accessed [today's date]).

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