Is EPS8 p.Arg77Gln (c.230G>A) pathogenic?

EPS8 p.Arg77Gln (c.230G>A) is classified Uncertain significance in EPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-30). AlphaMissense: ambiguous (0.3462); Ultra-rare (popmax 0.0332%, mid).

How common is EPS8 p.Arg77Gln (c.230G>A) in the general population?

EPS8 p.Arg77Gln (c.230G>A) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about EPS8 p.Arg77Gln (c.230G>A)?

AlphaMissense predicts ambiguous (score 0.3462) — an in-silico prediction, not a clinical call.

EPS8 p.Arg77Gln

c.230G>A · rs775251220 · VCV2074633

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3462 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3462	ambiguous
REVEL	0.111	moderately benign-leaning
SaProt	LLR -6.60	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.57	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 7.7	GERP 2.1, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	34.0	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 0.0332% Middle Eastern · 2/6,030 alleles

Filtering AF 0.0156% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0132%

Overall 0.00417% 67/1,605,924 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,015
South Asian	0.0235%	4,260
Remaining individualsnot grpmax-eligible	0.0145%	6,908
Admixed American	0.00347%	28,829
European (non-Finnish)	0.00272%	36,801
African / African-American	0.00134%	74,364

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.Arg77Gln
Coding: c.230G>A
MANE Select: NM_004447
dbSNP: rs775251220
Type: single nucleotide variant
Location: chr12:15669800 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 70.77 · 2 PDB
Residue 77: the ptb domain

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

Similar variants

EPS8 p.Arg77Gly Uncertain significance ★ ⚠ same residue
EPS8 p.Arg77Trp Uncertain significance ★ 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.Arg195Trp Uncertain significance ★★ ⚠ same type
EPS8 p.Arg403Trp 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-arg77gln (accessed [today's date]).

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