Is EYS p.Pro1631Ser (c.4891C>T) pathogenic?

EYS p.Pro1631Ser (c.4891C>T) is classified Conflicting classifications of pathogenicity in EYS (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-05-12). AlphaMissense: likely benign (0.108); Rare (popmax 0.173%, nfe); Associated with retinitis pigmentosa.

What condition is associated with EYS p.Pro1631Ser (c.4891C>T)?

EYS p.Pro1631Ser (c.4891C>T) is associated with retinitis pigmentosa, retinitis pigmentosa 25 (ClinVar).

How common is EYS p.Pro1631Ser (c.4891C>T) in the general population?

EYS p.Pro1631Ser (c.4891C>T) is rare (popmax 0.173%, nfe) (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.Pro1631Ser (c.4891C>T)?

AlphaMissense predicts likely benign (score 0.108) — an in-silico prediction, not a clinical call.

EYS p.Pro1631Ser

c.4891C>T · rs200935518 · VCV554129

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely benign

0.108 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.173%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

retinitis pigmentosa

Computational evidence

Protein change
AlphaMissense	0.108	likely benign
REVEL	0.196	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 0.59	phastCons 0.61
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	17.62	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 0.173% European (non-Finnish) · 1,982/1,146,746 alleles

Filtering AF 0.166% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.164%

Overall 0.138% 2,135/1,551,228 alleles · rare exomes 2,017/1,399,030 · genomes 118/152,198 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.173%	579
Middle Eastern	0.15%	666
Remaining individualsnot grpmax-eligible	0.11%	911
Admixed American	0.0765%	1,307
Finnishnot grpmax-eligible	0.0201%	4,982
African / African-American	0.0191%	5,224
South Asian	0.0143%	7,005
East Asian	0.00245%	40,896

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.Pro1631Ser
Coding: c.4891C>T
MANE Select: NM_001142800
dbSNP: rs200935518
Type: single nucleotide variant
Location: chr6:64590976 (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

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 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
EYS c.1185-1G>A Likely pathogenic ★★ same condition
EYS c.1299+2T>A Likely pathogenic ★★ same condition
EYS c.1599+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-pro1631ser (accessed [today's date]).

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