Is EPS8L2 p.Gln537Glu (c.1609C>G) pathogenic?

EPS8L2 p.Gln537Glu (c.1609C>G) is classified Uncertain significance in EPS8L2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-05-13). AlphaMissense: likely benign (0.0946); Rare (popmax 0.103%, amr).

How common is EPS8L2 p.Gln537Glu (c.1609C>G) in the general population?

EPS8L2 p.Gln537Glu (c.1609C>G) is rare (popmax 0.103%, amr) (gnomAD).

What do computational predictors say about EPS8L2 p.Gln537Glu (c.1609C>G)?

AlphaMissense predicts likely benign (score 0.0946) — an in-silico prediction, not a clinical call.

EPS8L2 p.Gln537Glu

c.1609C>G · rs377042373 · VCV2075224

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0946 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.103%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0946	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -8.61	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.5	GERP 0.62, phastCons 1
Regional constraint	o/e 1.19	unconstrained · MANE · 18 kb · p 2.2e-09 · regional, not allelic
Overall
CADD	23.4	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.103% Admixed American · 30/29,220 alleles

Filtering AF 0.0738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0641%

Overall 0.00985% 134/1,360,296 alleles · rare exomes 107/1,208,118 · genomes 27/152,178 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.103%	974
Remaining individualsnot grpmax-eligible	0.0156%	6,395
African / African-American	0.00902%	11,092
European (non-Finnish)	0.00849%	11,776

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: EPS8L2
Protein: p.Gln537Glu
Coding: c.1609C>G
MANE Select: NM_022772
dbSNP: rs377042373
Type: single nucleotide variant
Location: chr11:725776 (GRCh38)
Gene constraint: LOEUF 1.164 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.67 · 2 PDB
Residue 537: the sh3 domain

Full EPS8L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPS8L2 p.Glu165Ter Likely pathogenic ★★ same type
EPS8L2 p.Arg102Trp Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg193Gln Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg245Gln Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg272Trp Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg365Cys Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg506Leu Uncertain significance ★★ ⚠ same type
EPS8L2 p.Arg76Trp Uncertain significance ★★ ⚠ same type

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/eps8l2-p-gln537glu (accessed [today's date]).

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