Is EEA1 p.Ser1394Phe (c.4181C>T) pathogenic?

EEA1 p.Ser1394Phe (c.4181C>T) is classified Uncertain significance in EEA1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-01). AlphaMissense: ambiguous (0.3832); Very rare (popmax 0.00223%, eas).

How common is EEA1 p.Ser1394Phe (c.4181C>T) in the general population?

EEA1 p.Ser1394Phe (c.4181C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about EEA1 p.Ser1394Phe (c.4181C>T)?

AlphaMissense predicts ambiguous (score 0.3832) — an in-silico prediction, not a clinical call.

EEA1 p.Ser1394Phe

c.4181C>T · VCV3274532

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3832 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.3832	ambiguous
REVEL	0.677	pathogenic-leaning
SaProt	LLR -10.39	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 94 bp · p 0.12 · regional, not allelic
Overall
CADD	28.1	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 0.00223% East Asian · 1/44,750 alleles

Overall 6.2e-05% 1/1,611,624 alleles · very rare exomes 1/1,459,664 · genomes 0/151,960 · joint denominator

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: EEA1
Protein: p.Ser1394Phe
Coding: c.4181C>T
MANE Select: NM_003566
Type: single nucleotide variant
Location: chr12:92776066 (GRCh38)
Gene constraint: LOEUF 0.663 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 73.53 · 4 PDB
Residue 1394: a turn

Full EEA1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EEA1 p.Asn1072Lys Benign ★★ same type
EEA1 p.Tyr718= Benign ★★ same type
EEA1 c.3468+1G>A Uncertain significance ★ same type
EEA1 c.4015-1G>C Uncertain significance ★ same type
EEA1 p.Ala1092Val Uncertain significance ★ ⚠ same type
EEA1 p.Ala1184Val Uncertain significance ★ ⚠ same type
EEA1 p.Ala1245Val Uncertain significance ★ ⚠ same type
EEA1 p.Ala393Val 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/eea1-p-ser1394phe (accessed [today's date]).

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