Is CEP135 p.Lys459fs (c.1376_1379del) pathogenic?

CEP135 p.Lys459fs (c.13761379del) is classified Pathogenic in CEP135 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2020-05-26). Very rare (popmax 0.00329%, sas); Associated with microcephaly 8, primary, autosomal recessive.

What condition is associated with CEP135 p.Lys459fs (c.1376_1379del)?

CEP135 p.Lys459fs (c.1376_1379del) is associated with microcephaly 8, primary, autosomal recessive (ClinVar).

How common is CEP135 p.Lys459fs (c.1376_1379del) in the general population?

CEP135 p.Lys459fs (c.1376_1379del) is very rare (popmax 0.00329%, sas) (gnomAD).

CEP135 p.Lys459fs

c.1376_1379del · rs777869134 · VCV1012269

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00329%, sas)

Conditions

microcephaly 8, primary, autosomal recessive

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 26
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.19	GERP 0.69, phastCons 0.99
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00329% South Asian · 3/91,058 alleles

Filtering AF 0.000875% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000443%

Overall 0.000248% 4/1,613,836 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00329%	30,353
Admixed American	0.00167%	60,010

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.Lys459fs
Coding: c.1376_1379del
MANE Select: NM_025009
dbSNP: rs777869134
Type: Microsatellite
Location: chr4:55974868 (GRCh38)
Gene constraint: LOEUF 0.989 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.15 · 2 PDB

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

Disease context

microcephaly 8, primary, autosomal recessive — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CEP135 p.His661fs Likely pathogenic ★ same condition
CEP135 c.473-1G>C Likely pathogenic ★★ same condition
CEP135 p.Arg1083Ter Pathogenic/Likely pathogenic ★★ same condition
CEP135 p.Arg292Ter Pathogenic/Likely pathogenic ★★ same condition
CEP135 p.Arg418Ter Pathogenic ★★ same condition
CEP135 p.Arg470Ter Pathogenic/Likely pathogenic ★★ same condition
CEP135 p.Arg908Ter Pathogenic ★★ same condition
CEP135 p.Lys1043fs Pathogenic/Likely pathogenic ★★ same condition

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-lys459fs (accessed [today's date]).

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