Is DEFA6 p.Arg2Lys (c.5G>A) pathogenic?

DEFA6 p.Arg2Lys (c.5G>A) is classified Uncertain significance in DEFA6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-28). AlphaMissense: likely benign (0.1066); Ultra-rare (popmax 0.0335%, eas).

How common is DEFA6 p.Arg2Lys (c.5G>A) in the general population?

DEFA6 p.Arg2Lys (c.5G>A) is ultra-rare (popmax 0.0335%, eas) (gnomAD).

What do computational predictors say about DEFA6 p.Arg2Lys (c.5G>A)?

AlphaMissense predicts likely benign (score 0.1066) — an in-silico prediction, not a clinical call.

DEFA6 p.Arg2Lys

c.5G>A · VCV4010631

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1066 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0335%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1066	likely benign
REVEL	0.084	moderately benign-leaning
SaProt	LLR -5.33	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 -0.31	GERP -1.9, phastCons 0.014
Regional constraint	o/e 1.60	unconstrained · MANE · 1,214 bp · p 4.4e-11 · regional, not allelic
Overall
CADD	16.62	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 0.0335% East Asian · 15/44,764 alleles

Filtering AF 0.0206% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0167%

Overall 0.00435% 70/1,608,796 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0335%	2,984
European (non-Finnish)	0.00458%	21,815
Remaining individualsnot grpmax-eligible	0.00161%	62,258

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: DEFA6
Protein: p.Arg2Lys
Coding: c.5G>A
MANE Select: NM_001926
Type: single nucleotide variant
Location: chr8:6926031 (GRCh38)
Gene constraint: LOEUF 1.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.49 · 5 PDB

Full DEFA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFA6 p.Glu35Asp Benign ★★ same type
DEFA6 p.Ala14Asp Uncertain significance ★ ⚠ same type
DEFA6 p.Ala24Thr Uncertain significance ★ ⚠ same type
DEFA6 p.Ala33Gly Uncertain significance ★ ⚠ same type
DEFA6 p.Ala38Val Uncertain significance ★ ⚠ same type
DEFA6 p.Ala57Thr Uncertain significance ★ ⚠ same type
DEFA6 p.Ala63Pro Uncertain significance ★ ⚠ same type
DEFA6 p.Arg42Cys 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/defa6-p-arg2lys (accessed [today's date]).

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