Is EYS p.Phe59Val (c.175T>G) pathogenic?

EYS p.Phe59Val (c.175T>G) is classified Uncertain significance in EYS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-01-23). AlphaMissense: likely benign (0.1249); Ultra-rare (popmax 0.0133%, amr); Associated with Inborn genetic diseases.

What condition is associated with EYS p.Phe59Val (c.175T>G)?

EYS p.Phe59Val (c.175T>G) is associated with Inborn genetic diseases (ClinVar).

How common is EYS p.Phe59Val (c.175T>G) in the general population?

EYS p.Phe59Val (c.175T>G) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about EYS p.Phe59Val (c.175T>G)?

AlphaMissense predicts likely benign (score 0.1249) — an in-silico prediction, not a clinical call.

EYS p.Phe59Val

c.175T>G · rs761421057 · VCV2155105

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1249 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1249	likely benign
REVEL	0.224	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 -1.4	GERP -3.5
Regional constraint	o/e 1.08	unconstrained · MANE · 1,775 kb · p 4.6e-07 · regional, not allelic
Overall
CADD	0.042	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 0.0133% Admixed American · 8/60,002 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.00124% 20/1,614,078 alleles · ultra-rare exomes 14/1,461,854 · genomes 6/152,224 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,500
South Asian	0.00549%	18,219
Remaining individualsnot grpmax-eligible	0.0048%	20,829
East Asian	0.00446%	22,445
European (non-Finnish)	0.000169%	590,019

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.Phe59Val
Coding: c.175T>G
MANE Select: NM_001142800
dbSNP: rs761421057
Type: single nucleotide variant
Location: chr6:65495236 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

EYS p.Ala1174Glu Uncertain significance ★★ same condition
EYS p.Ala1465Thr Uncertain significance ★★ ⚠ same condition
EYS p.Ala1520Asp Uncertain significance ★★ ⚠ same condition
EYS p.Ala1520Gly Uncertain significance ★★ ⚠ same condition
EYS p.Ala1984Thr Uncertain significance ★★ same condition
EYS p.Ala2728Val Uncertain significance ★★ ⚠ same condition
EYS p.Ala2729Val Uncertain significance ★★ ⚠ same condition
EYS p.Ala315Thr Uncertain significance ★★ ⚠ 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-phe59val (accessed [today's date]).

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