Is CEP135 p.Leu1124Val (c.3370C>G) pathogenic?

CEP135 p.Leu1124Val (c.3370C>G) is classified Uncertain significance in CEP135 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-22). AlphaMissense: likely benign (0.0635); Very rare (popmax 8.48e-05%, nfe).

How common is CEP135 p.Leu1124Val (c.3370C>G) in the general population?

CEP135 p.Leu1124Val (c.3370C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CEP135 p.Leu1124Val (c.3370C>G)?

AlphaMissense predicts likely benign (score 0.0635) — an in-silico prediction, not a clinical call.

CEP135 p.Leu1124Val

c.3370C>G · VCV4717541

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0635 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0635	likely benign
REVEL	0.076	moderately benign-leaning
SaProt	LLR -6.73	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 2.2	GERP 0.79, phastCons 0.98
Regional constraint	o/e 1.01	unconstrained · MANE · 72 kb · p 0.83 · regional, not allelic
Overall
CADD	19.37	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,894 alleles

Overall 6.84e-05% 1/1,461,674 alleles · very rare

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: CEP135
Protein: p.Leu1124Val
Coding: c.3370C>G
MANE Select: NM_025009
Type: single nucleotide variant
Location: chr4:56024550 (GRCh38)
Gene constraint: LOEUF 0.989 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.15 · 2 PDB
Residue 1124: the 'disordered' region

Full CEP135 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CEP135 c.473-1G>C Likely pathogenic ★★ same type
CEP135 p.Arg1083Ter Pathogenic/Likely pathogenic ★★ same type
CEP135 p.Arg292Ter Pathogenic/Likely pathogenic ★★ same type
CEP135 p.Arg418Ter Pathogenic ★★ same type
CEP135 p.Arg470Ter Pathogenic/Likely pathogenic ★★ same type
CEP135 p.Arg908Ter Pathogenic ★★ same type
CEP135 p.Leu578Ter Pathogenic ★★ same type
CEP135 p.Lys1071Ter 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/cep135-p-leu1124val (accessed [today's date]).

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