Is DEFB4A p.Leu7Ile (c.19C>A) pathogenic?

DEFB4A p.Leu7Ile (c.19C>A) is classified Uncertain significance in DEFB4A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.1307); Very rare (popmax 0.00167%, amr).

How common is DEFB4A p.Leu7Ile (c.19C>A) in the general population?

DEFB4A p.Leu7Ile (c.19C>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DEFB4A p.Leu7Ile (c.19C>A)?

AlphaMissense predicts likely benign (score 0.1307) — an in-silico prediction, not a clinical call.

DEFB4A p.Leu7Ile

c.19C>A · VCV4829550

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1307 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1307	likely benign
REVEL	0.035	moderately benign-leaning
SaProt	LLR -7.73	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 0.59	GERP 1.2, phastCons 0.071
Regional constraint	o/e 0.05	constrained · MANE · 1,894 bp · p 7.4e-06 · regional, not allelic
Overall
CADD	10.68	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 0.00167% Admixed American · 1/59,866 alleles

Overall 6.85e-05% 1/1,460,656 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: DEFB4A
Protein: p.Leu7Ile
Coding: c.19C>A
MANE Select: NM_004942
Type: single nucleotide variant
Location: chr8:7894731 (GRCh38)
Gene constraint: LOEUF 1.85 · pLI 0.33 (gnomAD)
Structure: AlphaFold pLDDT 78.53 · 6 PDB

Full DEFB4A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFB4A p.Met16Ile Benign ★★ same type
DEFB4A p.Leu11Phe Uncertain significance ★ ⚠ same type
DEFB4A p.Leu32Arg Uncertain significance ★ ⚠ same type
DEFB4A p.Phe14Ile Uncertain significance ★ ⚠ same type
DEFB4A p.Pro17Ser Uncertain significance ★ ⚠ same type
DEFB4A p.Pro40Leu 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/defb4a-p-leu7ile (accessed [today's date]).

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