Is CEP295 p.Phe682Leu (c.2046T>G) pathogenic?

CEP295 p.Phe682Leu (c.2046T>G) is classified Uncertain significance in CEP295 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-20). AlphaMissense: likely pathogenic (0.6206); Ultra-rare (popmax 0.0157%, amr).

How common is CEP295 p.Phe682Leu (c.2046T>G) in the general population?

CEP295 p.Phe682Leu (c.2046T>G) is ultra-rare (popmax 0.0157%, amr) (gnomAD).

What do computational predictors say about CEP295 p.Phe682Leu (c.2046T>G)?

AlphaMissense predicts likely pathogenic (score 0.6206) — an in-silico prediction, not a clinical call.

CEP295 p.Phe682Leu

c.2046T>G · VCV3266167

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6206 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0157%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6206	likely pathogenic · top 5% in CEP295
REVEL	0.055	moderately benign-leaning
SaProt	LLR -5.00	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 1.5	GERP 1.6, phastCons 0.98
Regional constraint	o/e 0.98	unconstrained · MANE · 35 kb · p 0.4 · regional, not allelic
Overall
CADD	18.21	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 0.0157% Admixed American · 8/50,988 alleles

Filtering AF 0.00772% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.00129% 20/1,551,828 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0157%	6,373
Remaining individualsnot grpmax-eligible	0.00166%	60,172
European (non-Finnish)	0.000959%	104,278

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: CEP295
Protein: p.Phe682Leu
Coding: c.2046T>G
MANE Select: NM_033395
Type: single nucleotide variant
Location: chr11:93696958 (GRCh38)
Gene constraint: LOEUF 0.735 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.76
Residue 682: a UniProt-annotated variant site (in sckl11; likely pathogenic)

Full CEP295 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CEP295 p.Gln2146His Uncertain significance ★★ ⚠ same type
CEP295 p.Gln998Arg Uncertain significance ★★ ⚠ same type
CEP295 p.Thr451Arg Uncertain significance ★★ ⚠ same type
CEP295 p.Gln1506= Benign ★★ same type
CEP295 p.Gln1728= Benign ★★ same type
CEP295 p.Gln80Lys Benign ★★ same type
CEP295 p.Glu1026Lys Benign ★★ ⚠ same type
CEP295 p.Glu179Lys Benign ★★ 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/cep295-p-phe682leu (accessed [today's date]).

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