Is EDC4 p.Met667Val (c.1999A>G) pathogenic?

EDC4 p.Met667Val (c.1999A>G) is classified Uncertain significance in EDC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-06). AlphaMissense: likely benign (0.0606); Ultra-rare (popmax 0.0506%, sas).

How common is EDC4 p.Met667Val (c.1999A>G) in the general population?

EDC4 p.Met667Val (c.1999A>G) is ultra-rare (popmax 0.0506%, sas) (gnomAD).

What do computational predictors say about EDC4 p.Met667Val (c.1999A>G)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

EDC4 p.Met667Val

c.1999A>G · VCV4246538

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0506%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0606	likely benign
REVEL	0.026	moderately benign-leaning
SaProt	LLR -4.88	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 1.2	GERP -1.2, phastCons 0.086
Regional constraint	o/e 0.88	unconstrained · MANE · 1,809 bp · p 0.01 · regional, not allelic
Overall
CADD	9.33	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 0.0506% South Asian · 46/90,962 alleles

Filtering AF 0.039% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0348%

Overall 0.00353% 57/1,612,774 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0506%	1,977
East Asian	0.00446%	22,431
Remaining individualsnot grpmax-eligible	0.0032%	31,226
European (non-Finnish)	0.000594%	168,485

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: EDC4
Protein: p.Met667Val
Coding: c.1999A>G
MANE Select: NM_014329
Type: single nucleotide variant
Location: chr16:67880118 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.59 (gnomAD)
Structure: AlphaFold pLDDT 63.18
Residue 667: the 'disordered' region

Full EDC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

EDC4 p.Met667Leu Uncertain significance ★ ⚠ same residue
EDC4 p.Gly309= Benign ★★ same type
EDC4 p.Ala1030Val Uncertain significance ★ ⚠ same type
EDC4 p.Ala1036Thr Uncertain significance ★ ⚠ same type
EDC4 p.Ala1076Thr Uncertain significance ★ ⚠ same type
EDC4 p.Ala1117Asp Uncertain significance ★ ⚠ same type
EDC4 p.Ala1284Val Uncertain significance ★ ⚠ same type
EDC4 p.Ala26Gly 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/edc4-p-met667val (accessed [today's date]).

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