Is EPS8 p.Lys193Met (c.578A>T) pathogenic?

EPS8 p.Lys193Met (c.578A>T) is classified Uncertain significance in EPS8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-07-15). AlphaMissense: ambiguous (0.5628); Very rare (popmax 0.004%, afr).

How common is EPS8 p.Lys193Met (c.578A>T) in the general population?

EPS8 p.Lys193Met (c.578A>T) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about EPS8 p.Lys193Met (c.578A>T)?

AlphaMissense predicts ambiguous (score 0.5628) — an in-silico prediction, not a clinical call.

EPS8 p.Lys193Met

c.578A>T · rs149392794 · VCV1309862

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5628 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5628	ambiguous
REVEL	0.141	moderately benign-leaning
SaProt	LLR -10.51	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 2.3, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	24.7	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 0.004% African / African-American · 3/74,950 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000682% 11/1,613,792 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,983
Remaining individualsnot grpmax-eligible	0.0016%	62,478
European (non-Finnish)	0.000593%	168,540

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.Lys193Met
Coding: c.578A>T
MANE Select: NM_004447
dbSNP: rs149392794
Type: single nucleotide variant
Location: chr12:15666461 (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 193: the ptb domain

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-lys193met (accessed [today's date]).

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