Is DEF6 p.Arg425Gln (c.1274G>A) pathogenic?

DEF6 p.Arg425Gln (c.1274G>A) is classified Uncertain significance in DEF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-14). AlphaMissense: likely benign (0.0738); Very rare (popmax 0.00223%, eas).

How common is DEF6 p.Arg425Gln (c.1274G>A) in the general population?

DEF6 p.Arg425Gln (c.1274G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DEF6 p.Arg425Gln (c.1274G>A)?

AlphaMissense predicts likely benign (score 0.0738) — an in-silico prediction, not a clinical call.

DEF6 p.Arg425Gln

c.1274G>A · rs766579626 · VCV1471466

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0738 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0738	likely benign
REVEL	0.036	moderately benign-leaning
SaProt	LLR -6.18	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 4.4	GERP 1, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 24 kb · p 1.6e-17 · regional, not allelic
Overall
CADD	20.1	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 0.00223% East Asian · 1/44,864 alleles

Overall 6.84e-05% 1/1,461,704 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: DEF6
Protein: p.Arg425Gln
Coding: c.1274G>A
MANE Select: NM_022047
dbSNP: rs766579626
Type: single nucleotide variant
Location: chr6:35319582 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 425: a UniProt-annotated variant site (in imd87; protein not detected in homozygous patient t cells or when the mutant is expressed in a heterologous system)

Full DEF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEF6 p.Arg425Leu Uncertain significance ★ ⚠ same residue
DEF6 p.Ala395Glu Uncertain significance ★★ ⚠ same type
DEF6 p.Ala617Val Uncertain significance ★★ ⚠ same type
DEF6 p.Arg104Pro Uncertain significance ★★ ⚠ same type
DEF6 p.Arg104Trp Uncertain significance ★★ ⚠ same type
DEF6 p.Arg192Cys Uncertain significance ★★ ⚠ same type
DEF6 p.Arg195Gln Uncertain significance ★★ ⚠ same type
DEF6 p.Arg349Leu 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/def6-p-arg425gln (accessed [today's date]).

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