Is CERKL p.Ser321fs (c.954_961dup) pathogenic?

CERKL p.Ser321fs (c.954961dup) is classified Pathogenic in CERKL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-30). Very rare (popmax 0.00667%, amr); Associated with CERKL-related disorders.

What condition is associated with CERKL p.Ser321fs (c.954_961dup)?

CERKL p.Ser321fs (c.954_961dup) is associated with CERKL-related disorders, retinitis pigmentosa 26 (ClinVar).

How common is CERKL p.Ser321fs (c.954_961dup) in the general population?

CERKL p.Ser321fs (c.954_961dup) is very rare (popmax 0.00667%, amr) (gnomAD).

CERKL p.Ser321fs

c.954_961dup · rs758116997 · VCV1072129

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

CERKL-related disorders

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 7 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.6	GERP 1.6, phastCons 1
Overall
CADD	35.0	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 0.00667% Admixed American · 4/59,972 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,613,926 alleles · very rare exomes 3/1,461,706 · genomes 1/152,220 · joint denominator

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: CERKL
Protein: p.Ser321fs
Coding: c.954_961dup
MANE Select: NM_201548
dbSNP: rs758116997
Type: Duplication
Location: chr2:181548791 (GRCh38)
Gene constraint: LOEUF 1.43 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.82
Residue 321: the dagkc domain

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

Disease context

CERKL-related disorders

Also linked: retinitis pigmentosa 26

Similar variants

CERKL p.Asn454fs Pathogenic/Likely pathogenic ★★ same condition
CERKL p.Leu216fs Pathogenic/Likely pathogenic ★★ same condition
CERKL p.Ser520fs Likely pathogenic ★★ same condition
CERKL p.Thr465fs Pathogenic ★★ same condition
CERKL p.Tyr522fs Pathogenic/Likely pathogenic ★★ same condition
CERKL c.239-4dup Benign ★★ same condition
CERKL p.Ala280fs Likely pathogenic ★ same condition
CERKL p.Ile512fs 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/cerkl-p-ser321fs (accessed [today's date]).

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