Is EYS p.Ser1367Pro (c.4099T>C) pathogenic?

EYS p.Ser1367Pro (c.4099T>C) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-12). AlphaMissense: likely benign (0.0972); Very rare (popmax 0.00196%, amr); Associated with retinitis pigmentosa.

What condition is associated with EYS p.Ser1367Pro (c.4099T>C)?

EYS p.Ser1367Pro (c.4099T>C) is associated with retinitis pigmentosa (ClinVar).

How common is EYS p.Ser1367Pro (c.4099T>C) in the general population?

EYS p.Ser1367Pro (c.4099T>C) is very rare (popmax 0.00196%, amr) (gnomAD).

How is Retinitis pigmentosa inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about EYS p.Ser1367Pro (c.4099T>C)?

AlphaMissense predicts likely benign (score 0.0972) — an in-silico prediction, not a clinical call.

EYS p.Ser1367Pro

c.4099T>C · rs1285964857 · VCV909838

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0972 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.0972	likely benign
REVEL	0.466	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.56
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	14.39	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% Admixed American · 1/50,976 alleles

Filtering AF 8.2e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.5e-05%

Overall 0.000322% 5/1,551,342 alleles · very rare exomes 5/1,399,092 · genomes 0/152,250 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00196%	50,976
European (non-Finnish)	0.000349%	286,686

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.Ser1367Pro
Coding: c.4099T>C
MANE Select: NM_001142800
dbSNP: rs1285964857
Type: single nucleotide variant
Location: chr6:64591768 (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

retinitis pigmentosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Retinitis pigmentosa (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Mitochondrial inheritance
Onset: Adolescent, Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

EYS p.Ser1367Ter Likely pathogenic ★ same residue
EYS p.Ser1367Leu Uncertain significance ★★ same residue
EYS p.Ser1367= Likely benign ★ same residue
EYS c.1056+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.1766+1G>T Pathogenic/Likely pathogenic ★★ same condition
EYS c.2259+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.3164+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.3243+1G>A 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-ser1367pro (accessed [today's date]).

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