Is EYS p.Pro321fs (c.962del) pathogenic?

EYS p.Pro321fs (c.962del) is classified Pathogenic/Likely pathogenic in EYS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-22). Very rare (popmax 8.48e-05%, nfe); Associated with EYS-related disorder.

What condition is associated with EYS p.Pro321fs (c.962del)?

EYS p.Pro321fs (c.962del) is associated with EYS-related disorder (ClinVar).

How common is EYS p.Pro321fs (c.962del) in the general population?

EYS p.Pro321fs (c.962del) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

EYS p.Pro321fs

c.962del · rs1766681441 · VCV2036122

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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

Conditions

EYS-related disorder

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 6 of 43
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.14	GERP 1.1
Overall
CADD	14.45	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 8.48e-05% European (non-Finnish) · 1/1,179,522 alleles

Overall 6.2e-05% 1/1,613,212 alleles · very rare exomes 0/1,461,250 · genomes 1/151,962 · 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: EYS
Protein: p.Pro321fs
Coding: c.962del
MANE Select: NM_001142800
dbSNP: rs1766681441
Type: Deletion
Location: chr6:65405268 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)

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

Disease context

EYS-related disorder

Similar variants

EYS p.Ala2957fs Pathogenic/Likely pathogenic ★★ same condition
EYS p.Asn1773_Val1781delinsLys Pathogenic/Likely pathogenic ★★ same condition
EYS p.Asn2918fs Pathogenic/Likely pathogenic ★★ same condition
EYS p.Asn328fs Pathogenic/Likely pathogenic ★★ same condition
EYS p.Cys412fs Pathogenic/Likely pathogenic ★★ same condition
EYS p.Cys78fs Pathogenic ★★ same condition
EYS p.Gln2723fs Pathogenic/Likely pathogenic ★★ same condition
EYS p.Gln3053fs 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/eys-p-pro321fs (accessed [today's date]).

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