Is EYS p.Val74fs (c.220del) pathogenic?

EYS p.Val74fs (c.220del) is classified Likely pathogenic in EYS (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-22). Very rare (popmax 0.00934%, afr); Associated with EYS-related disorder.

What condition is associated with EYS p.Val74fs (c.220del)?

EYS p.Val74fs (c.220del) is associated with EYS-related disorder (ClinVar).

How common is EYS p.Val74fs (c.220del) in the general population?

EYS p.Val74fs (c.220del) is very rare (popmax 0.00934%, afr) (gnomAD).

EYS p.Val74fs

c.220del · rs1375767063 · VCV866810

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

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 4 of 43
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.2	GERP 0.28, phastCons 0.15
Overall
CADD	17.82	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 0.00934% African / African-American · 7/74,940 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000434% 7/1,614,058 alleles · very rare exomes 2/1,461,816 · genomes 5/152,242 · 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.Val74fs
Coding: c.220del
MANE Select: NM_001142800
dbSNP: rs1375767063
Type: Deletion
Location: chr6:65495191 (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-val74fs (accessed [today's date]).

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