Is EPHA2 p.Ser899= (c.2697C>T) pathogenic?

EPHA2 p.Ser899= (c.2697C>T) is classified Uncertain significance in EPHA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-01-13). Very rare (popmax 0.00297%, nfe); Associated with cataract 6 multiple types.

What condition is associated with EPHA2 p.Ser899= (c.2697C>T)?

EPHA2 p.Ser899= (c.2697C>T) is associated with cataract 6 multiple types (ClinVar).

How common is EPHA2 p.Ser899= (c.2697C>T) in the general population?

EPHA2 p.Ser899= (c.2697C>T) is very rare (popmax 0.00297%, nfe) (gnomAD).

How is Early onset non-syndromic cataract inherited?

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

EPHA2 p.Ser899=

c.2697C>T · rs749180343 · VCV873861

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00297%, nfe)

Conditions

cataract 6 multiple types

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -7.8	GERP -4.2
Overall
CADD	3.24	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00297% European (non-Finnish) · 35/1,179,922 alleles

Filtering AF 0.00215% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00191%

Overall 0.00248% 40/1,612,344 alleles · very rare exomes 35/1,460,212 · genomes 5/152,132 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,598
Finnishnot grpmax-eligible	0.0032%	31,261
European (non-Finnish)grpmax	0.00297%	33,712
African / African-American	0.00267%	37,447

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: EPHA2
Protein: p.Ser899=
Coding: c.2697C>T
MANE Select: NM_004431
dbSNP: rs749180343
Type: single nucleotide variant
Location: chr1:16129562 (GRCh38)
Gene constraint: LOEUF 0.652 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.73 · 103 PDB
Residue 899: the 'mediates interaction with arhgef16 and elmo2' region; the 'negatively regulates interaction with arhgef16' region

Full EPHA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cataract 6 multiple types — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Early onset non-syndromic cataract (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Infancy, Neonatal

Similar variants

EPHA2 c.2826-9G>A Pathogenic ★★ same condition
EPHA2 p.Ala321Val Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg175His Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg195Cys Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg315Trp Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg428His Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg560His Uncertain significance ★★ ⚠ same condition
EPHA2 p.Arg566His 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/epha2-p-ser899 (accessed [today's date]).

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