Is ECD p.Glu40Lys (c.118G>A) pathogenic?

ECD p.Glu40Lys (c.118G>A) is classified Uncertain significance in ECD (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-08). AlphaMissense: likely benign (0.1482); Very rare (popmax 0.00333%, amr).

How common is ECD p.Glu40Lys (c.118G>A) in the general population?

ECD p.Glu40Lys (c.118G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about ECD p.Glu40Lys (c.118G>A)?

AlphaMissense predicts likely benign (score 0.1482) — an in-silico prediction, not a clinical call.

ECD p.Glu40Lys

c.118G>A · VCV4662884

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1482 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1482	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -7.97	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 3.3	GERP 2, phastCons 1
Overall
CADD	25.4	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 0.00333% Admixed American · 2/60,000 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000372% 6/1,614,150 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,000
Remaining individualsnot grpmax-eligible	0.0032%	31,253
European (non-Finnish)	0.000169%	590,009

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: ECD
Protein: p.Glu40Lys
Coding: c.118G>A
MANE Select: NM_006304 · reported on NM_007265
Type: single nucleotide variant
Location: chr10:73163820 (GRCh38)
Structure: AlphaFold pLDDT 69.87 · 140 PDB
Residue 40: a β-strand; the 'disordered' region

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

Similar variants

ECD p.Ala121Gly Uncertain significance ★ same type
ECD p.Ala122Ser Uncertain significance ★ ⚠ same type
ECD p.Ala150Thr Uncertain significance ★ ⚠ same type
ECD p.Ala234Ser Uncertain significance ★ ⚠ same type
ECD p.Ala329Val Uncertain significance ★ ⚠ same type
ECD p.Arg188Leu Uncertain significance ★ ⚠ same type
ECD p.Arg244Gln Uncertain significance ★ ⚠ same type
ECD p.Arg281Gln 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/ecd-p-glu40lys (accessed [today's date]).

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