Is EYS p.Arg667His (c.2000G>A) pathogenic?

EYS p.Arg667His (c.2000G>A) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 9 submitters; last evaluated 2024-10-30). AlphaMissense: likely benign (0.0895); Rare (popmax 0.144%, afr); Associated with retinitis pigmentosa.

What condition is associated with EYS p.Arg667His (c.2000G>A)?

EYS p.Arg667His (c.2000G>A) is associated with retinitis pigmentosa, retinitis pigmentosa 25 (ClinVar).

How common is EYS p.Arg667His (c.2000G>A) in the general population?

EYS p.Arg667His (c.2000G>A) is rare (popmax 0.144%, afr) (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.Arg667His (c.2000G>A)?

AlphaMissense predicts likely benign (score 0.0895) — an in-silico prediction, not a clinical call.

EYS p.Arg667His

c.2000G>A · rs549456693 · VCV438193

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0895 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.144%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.0895	likely benign
REVEL	0.217	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.091	GERP -0.22
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	19.83	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.144% African / African-American · 105/72,988 alleles

Filtering AF 0.122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.113%

Overall 0.0285% 441/1,547,622 alleles · rare exomes 344/1,395,852 · genomes 97/151,770 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.144%	695
Middle Eastern	0.134%	748
Admixed American	0.069%	1,450
Remaining individualsnot grpmax-eligible	0.0467%	2,142
European (non-Finnish)	0.0224%	4,473
East Asian	0.0196%	5,093
South Asian	0.00121%	82,782

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.Arg667His
Coding: c.2000G>A
MANE Select: NM_001142800
dbSNP: rs549456693
Type: single nucleotide variant
Location: chr6:65295886 (GRCh38)
Gene constraint: LOEUF 0.96 · pLI <0.01 (gnomAD)
Residue 667: the egf-like 7 domain

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

Also linked: retinitis pigmentosa 25

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.Arg667Leu Uncertain significance ★★ ⚠ same residue
EYS p.Arg667Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
EYS p.Arg667Pro Uncertain significance ★ ⚠ same residue
EYS c.1056+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.1056+3A>C Likely pathogenic ★★ same condition
EYS c.1057-1G>A Likely pathogenic ★★ same condition
EYS c.1184+1G>A Pathogenic/Likely pathogenic ★★ same condition
EYS c.1184+1G>T 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-arg667his (accessed [today's date]).

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