Is DEF6 p.Ala422= (c.1266C>G) pathogenic?

DEF6 p.Ala422= (c.1266C>G) is classified Likely benign in DEF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-23). Very rare (popmax 0.00167%, amr).

How common is DEF6 p.Ala422= (c.1266C>G) in the general population?

DEF6 p.Ala422= (c.1266C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

DEF6 p.Ala422=

c.1266C>G · rs575156362 · VCV1969431

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.51	GERP 1.1, phastCons 1
Overall
CADD	12.69	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/59,984 alleles

Overall 0.000657% 1/152,224 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.Ala422=
Coding: c.1266C>G
MANE Select: NM_022047
dbSNP: rs575156362
Type: single nucleotide variant
Location: chr6:35319574 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 422: 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.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
DEF6 p.Arg4Cys 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-ala422 (accessed [today's date]).

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