Is EPS8 p.Arg656His (c.1967G>A) pathogenic?

EPS8 p.Arg656His (c.1967G>A) is classified Uncertain significance in EPS8 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-02-12). AlphaMissense: likely benign (0.1601); Ultra-rare (popmax 0.0567%, nfe).

How common is EPS8 p.Arg656His (c.1967G>A) in the general population?

EPS8 p.Arg656His (c.1967G>A) is ultra-rare (popmax 0.0567%, nfe) (gnomAD).

What do computational predictors say about EPS8 p.Arg656His (c.1967G>A)?

AlphaMissense predicts likely benign (score 0.1601) — an in-silico prediction, not a clinical call.

EPS8 p.Arg656His

c.1967G>A · rs149793749 · VCV1334355

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1601 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0567%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1601	likely benign
REVEL	0.141	moderately benign-leaning
SaProt	LLR -6.03	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 5.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	27.5	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 0.0567% European (non-Finnish) · 669/1,179,990 alleles

Filtering AF 0.0531% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0517%

Overall 0.0437% 705/1,613,830 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0567%	1,764
Remaining individualsnot grpmax-eligible	0.0288%	3,471
African / African-American	0.012%	8,314
Admixed American	0.01%	9,998
South Asian	0.0022%	45,535
Finnishnot grpmax-eligible	0.00156%	63,984

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.Arg656His
Coding: c.1967G>A
MANE Select: NM_004447
dbSNP: rs149793749
Type: single nucleotide variant
Location: chr12:15631519 (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 656: the 'disordered' region; the 'effector region' region

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

Similar variants

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
EPS8 p.Arg432Gln Uncertain significance ★★ ⚠ same type
EPS8 p.Arg434Cys 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-arg656his (accessed [today's date]).

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