Is EPS8 p.Thr477= (c.1431A>G) pathogenic?

EPS8 p.Thr477= (c.1431A>G) is classified Likely benign in EPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-10). Rare (popmax 0.143%, sas).

How common is EPS8 p.Thr477= (c.1431A>G) in the general population?

EPS8 p.Thr477= (c.1431A>G) is rare (popmax 0.143%, sas) (gnomAD).

EPS8 p.Thr477=

c.1431A>G · VCV4754880

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.143%, sas)

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 -3.8	GERP -3.8
Overall
CADD	1.068	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.143% South Asian · 130/90,980 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.115%

Overall 0.00831% 134/1,613,376 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.143%	700
Remaining individualsnot grpmax-eligible	0.0064%	15,620

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.Thr477=
Coding: c.1431A>G
MANE Select: NM_004447
Type: single nucleotide variant
Location: chr12:15650826 (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 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-thr477 (accessed [today's date]).

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