Is ECI2 p.Glu147Lys (c.439G>A) pathogenic?

ECI2 p.Glu147Lys (c.439G>A) is classified Uncertain significance in ECI2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-23). AlphaMissense: likely benign (0.0824); Ultra-rare (popmax 0.0395%, sas).

How common is ECI2 p.Glu147Lys (c.439G>A) in the general population?

ECI2 p.Glu147Lys (c.439G>A) is ultra-rare (popmax 0.0395%, sas) (gnomAD).

What do computational predictors say about ECI2 p.Glu147Lys (c.439G>A)?

AlphaMissense predicts likely benign (score 0.0824) — an in-silico prediction, not a clinical call.

ECI2 p.Glu147Lys

c.439G>A · VCV3506493

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0824 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0395%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0824	likely benign
REVEL	0.119	moderately benign-leaning
SaProt	LLR -9.21	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.026	GERP -0.52
Regional constraint	o/e 0.99	unconstrained · MANE · 20 kb · p 0.84 · regional, not allelic
Overall
CADD	18.92	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 0.0395% South Asian · 36/91,084 alleles

Filtering AF 0.0293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0258%

Overall 0.0044% 71/1,614,200 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0395%	2,530
Remaining individualsnot grpmax-eligible	0.0064%	15,628
European (non-Finnish)	0.00237%	42,144
East Asian	0.00223%	44,886
Admixed American	0.00167%	60,030
African / African-American	0.00133%	75,054

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: ECI2
Protein: p.Glu147Lys
Coding: c.439G>A
MANE Select: NM_206836
Type: single nucleotide variant
Location: chr6:4130434 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.40 · 5 PDB
Residue 147: a β-strand

Full ECI2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ECI2 p.Ala67Val Uncertain significance ★ ⚠ same type
ECI2 p.Ala7Val Uncertain significance ★ ⚠ same type
ECI2 p.Ala95Thr Uncertain significance ★ ⚠ same type
ECI2 p.Arg157Trp Uncertain significance ★ ⚠ same type
ECI2 p.Cys15Tyr Uncertain significance ★ ⚠ same type
ECI2 p.Glu60Lys 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/eci2-p-glu147lys (accessed [today's date]).

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