Is EDC4 p.Val1229Met (c.3685G>A) pathogenic?

EDC4 p.Val1229Met (c.3685G>A) is classified Uncertain significance in EDC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-06). AlphaMissense: likely benign (0.0915); Ultra-rare (popmax 0.0114%, nfe).

How common is EDC4 p.Val1229Met (c.3685G>A) in the general population?

EDC4 p.Val1229Met (c.3685G>A) is ultra-rare (popmax 0.0114%, nfe) (gnomAD).

What do computational predictors say about EDC4 p.Val1229Met (c.3685G>A)?

AlphaMissense predicts likely benign (score 0.0915) — an in-silico prediction, not a clinical call.

EDC4 p.Val1229Met

c.3685G>A · rs781090608 · VCV2494608

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0915 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0114%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0915	likely benign
REVEL	0.044	moderately benign-leaning
SaProt	LLR -7.41	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.23	donor gain · deltas
Constraint at this position
Conservation	phyloP 8.2	GERP 1.7, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 3,251 bp · p 6.4e-17 · regional, not allelic
Overall
CADD	23.5	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 0.0114% European (non-Finnish) · 135/1,180,036 alleles

Filtering AF 0.00986% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0092%

Overall 0.0088% 142/1,613,968 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0114%	8,741
Remaining individualsnot grpmax-eligible	0.0064%	15,622
African / African-American	0.004%	24,980

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.Val1229Met
Coding: c.3685G>A
MANE Select: NM_014329
dbSNP: rs781090608
Type: single nucleotide variant
Location: chr16:67883013 (GRCh38)
Gene constraint: LOEUF 0.494 · pLI 0.59 (gnomAD)
Structure: AlphaFold pLDDT 63.18

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

Similar variants

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
EDC4 p.Ala315Val 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-val1229met (accessed [today's date]).

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