Is EPS8 p.Arg195Gln (c.584G>A) pathogenic?

EPS8 p.Arg195Gln (c.584G>A) is classified Uncertain significance in EPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-22). AlphaMissense: likely pathogenic (0.8103); Very rare (popmax 0.00934%, afr).

How common is EPS8 p.Arg195Gln (c.584G>A) in the general population?

EPS8 p.Arg195Gln (c.584G>A) is very rare (popmax 0.00934%, afr) (gnomAD).

What do computational predictors say about EPS8 p.Arg195Gln (c.584G>A)?

AlphaMissense predicts likely pathogenic (score 0.8103) — an in-silico prediction, not a clinical call.

EPS8 p.Arg195Gln

c.584G>A · VCV4915786

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8103 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00934%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8103	likely pathogenic
REVEL	0.208	benign-leaning
SaProt	LLR -15.43	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00934% African / African-American · 7/74,908 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00372%

Overall 0.0062% 100/1,613,352 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0507%	1,973
Remaining individualsnot grpmax-eligible	0.0112%	8,922
African / African-Americangrpmax	0.00934%	10,701
European (non-Finnish)	0.00517%	19,336
Admixed American	0.005%	19,999
Finnishnot grpmax-eligible	0.00469%	21,337
South Asian	0.00439%	22,765

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: EPS8
Protein: p.Arg195Gln
Coding: c.584G>A
MANE Select: NM_004447
Type: single nucleotide variant
Location: chr12:15666455 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.77 · 2 PDB

Full EPS8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EPS8 p.Arg195Trp Uncertain significance ★★ ⚠ same residue
EPS8 p.Arg195= Likely benign ★ same residue
EPS8 c.205-8A>G Uncertain significance ★★ same type
EPS8 p.Ala150Val Uncertain significance ★★ ⚠ same type
EPS8 p.Ala219Val Uncertain significance ★★ ⚠ same type
EPS8 p.Ala416Asp Uncertain significance ★★ ⚠ same type
EPS8 p.Arg403Trp Uncertain significance ★★ ⚠ same type
EPS8 p.Arg432Gln 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/eps8-p-arg195gln (accessed [today's date]).

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