Is EDC4 p.Phe232Leu (c.696T>G) pathogenic?

EDC4 p.Phe232Leu (c.696T>G) is classified Uncertain significance in EDC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely pathogenic (0.6611); Very rare (popmax 0.000169%, nfe).

How common is EDC4 p.Phe232Leu (c.696T>G) in the general population?

EDC4 p.Phe232Leu (c.696T>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about EDC4 p.Phe232Leu (c.696T>G)?

AlphaMissense predicts likely pathogenic (score 0.6611) — an in-silico prediction, not a clinical call.

EDC4 p.Phe232Leu

c.696T>G · VCV3843404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6611 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6611	likely pathogenic
REVEL	0.167	moderately benign-leaning
SaProt	LLR -2.40	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	Δ0.50	acceptor loss, 6 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 0.27	GERP -1.7, phastCons 0.98
Regional constraint	o/e 0.64	unconstrained · MANE · 1,766 bp · p 4.5e-12 · regional, not allelic
Overall
CADD	15.36	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 0.000169% European (non-Finnish) · 2/1,180,030 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,886 alleles · very rare

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.Phe232Leu
Coding: c.696T>G
MANE Select: NM_014329
Type: single nucleotide variant
Location: chr16:67877563 (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-phe232leu (accessed [today's date]).

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