Is CEP85 p.Arg475Cys (c.1423C>T) pathogenic?

CEP85 p.Arg475Cys (c.1423C>T) is classified Uncertain significance in CEP85 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely pathogenic (0.9381); Ultra-rare (popmax 0.0164%, mid).

How common is CEP85 p.Arg475Cys (c.1423C>T) in the general population?

CEP85 p.Arg475Cys (c.1423C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about CEP85 p.Arg475Cys (c.1423C>T)?

AlphaMissense predicts likely pathogenic (score 0.9381) — an in-silico prediction, not a clinical call.

CEP85 p.Arg475Cys

c.1423C>T · VCV3490934

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9381 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9381	likely pathogenic · top 5% in CEP85
REVEL	0.265	benign-leaning
SaProt	LLR -9.97	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 0.88, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 38 kb · p 0.075 · regional, not allelic
Overall
CADD	34.0	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 0.0164% Middle Eastern · 1/6,080 alleles

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

Overall 0.000744% 12/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
African / African-American	0.00267%	37,445
East Asian	0.00223%	44,898
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)	0.000508%	196,660

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: CEP85
Protein: p.Arg475Cys
Coding: c.1423C>T
MANE Select: NM_001319944
Type: single nucleotide variant
Location: chr1:26268564 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.09 · 2 PDB
Residue 475: the 'required for centrosome localization and for its function in the suppression of centrosome disjunction' region

Full CEP85 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CEP85 p.Ala176= Benign ★★ same type
CEP85 p.Leu405Phe Benign ★★ same type
CEP85 p.Ala374Pro Uncertain significance ★ ⚠ same type
CEP85 p.Ala396Thr Uncertain significance ★ ⚠ same type
CEP85 p.Ala399Ser Uncertain significance ★ ⚠ same type
CEP85 p.Ala656Val Uncertain significance ★ ⚠ same type
CEP85 p.Arg146Lys Uncertain significance ★ ⚠ same type
CEP85 p.Arg177Lys Uncertain significance ★ ⚠ 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/cep85-p-arg475cys (accessed [today's date]).

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