Is EEIG1 p.Ser227Phe (c.680C>T) pathogenic?

EEIG1 p.Ser227Phe (c.680C>T) is classified Uncertain significance in EEIG1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-14). AlphaMissense: ambiguous (0.4561); Very rare (popmax 8.54e-05%, nfe).

How common is EEIG1 p.Ser227Phe (c.680C>T) in the general population?

EEIG1 p.Ser227Phe (c.680C>T) is very rare (popmax 8.54e-05%, nfe) (gnomAD).

What do computational predictors say about EEIG1 p.Ser227Phe (c.680C>T)?

AlphaMissense predicts ambiguous (score 0.4561) — an in-silico prediction, not a clinical call.

EEIG1 p.Ser227Phe

c.680C>T · rs1350462462 · VCV3087370

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4561 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.54e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4561	ambiguous
REVEL	0.201	benign-leaning
SaProt	LLR -13.27	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 12	GERP 2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 4,940 bp · p 0.025 · regional, not allelic
Overall
CADD	24.1	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 8.54e-05% European (non-Finnish) · 1/1,170,692 alleles

Overall 6.28e-05% 1/1,593,062 alleles · very rare exomes 1/1,440,704 · genomes 0/152,358 · 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: EEIG1
Protein: p.Ser227Phe
Coding: c.680C>T
MANE Select: NM_001035254
dbSNP: rs1350462462
Type: single nucleotide variant
Location: chr9:127945690 (GRCh38)
Structure: AlphaFold pLDDT 69.30
Residue 227: the 'disordered' region

Full EEIG1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EEIG1 p.Ala326Val Uncertain significance ★ ⚠ same type
EEIG1 p.Arg118His Uncertain significance ★ ⚠ same type
EEIG1 p.Arg194Gln Uncertain significance ★ ⚠ same type
EEIG1 p.Arg228Gly Uncertain significance ★ ⚠ same type
EEIG1 p.Arg248Cys Uncertain significance ★ ⚠ same type
EEIG1 p.Arg258His Uncertain significance ★ ⚠ same type
EEIG1 p.Arg259Gly Uncertain significance ★ ⚠ same type
EEIG1 p.Arg283Gln 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/eeig1-p-ser227phe (accessed [today's date]).

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