Is EPS8 p.Ala418Thr (c.1252G>A) pathogenic?

EPS8 p.Ala418Thr (c.1252G>A) is classified Uncertain significance in EPS8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-08). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.00246%, nfe).

How common is EPS8 p.Ala418Thr (c.1252G>A) in the general population?

EPS8 p.Ala418Thr (c.1252G>A) is very rare (popmax 0.00246%, nfe) (gnomAD).

What do computational predictors say about EPS8 p.Ala418Thr (c.1252G>A)?

AlphaMissense predicts likely benign (score 0.0765) — an in-silico prediction, not a clinical call.

EPS8 p.Ala418Thr

c.1252G>A · rs1411062887 · VCV1516641

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0765 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00246%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0765	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -5.79	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.40 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.23	GERP -2.5, phastCons 0.23
Regional constraint	o/e 0.96	unconstrained · MANE · 62 kb · p 0.26 · regional, not allelic
Overall
CADD	13.62	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 0.00246% European (non-Finnish) · 29/1,179,378 alleles

Filtering AF 0.00172% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00219% 32/1,460,496 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00246%	40,668
Admixed American	0.00167%	59,852
Remaining individualsnot grpmax-eligible	0.0016%	62,464
African / African-American	0.00133%	74,976

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.Ala418Thr
Coding: c.1252G>A
MANE Select: NM_004447
dbSNP: rs1411062887
Type: single nucleotide variant
Location: chr12:15651005 (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-ala418thr (accessed [today's date]).

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