Is DEF6 p.Ala408= (c.1224C>T) pathogenic?

DEF6 p.Ala408= (c.1224C>T) is classified Likely benign in DEF6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0751%, nfe).

How common is DEF6 p.Ala408= (c.1224C>T) in the general population?

DEF6 p.Ala408= (c.1224C>T) is ultra-rare (popmax 0.0751%, nfe) (gnomAD).

DEF6 p.Ala408=

c.1224C>T · rs138908911 · VCV1299030

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0751%, nfe)

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 -0.11	GERP -0.053, phastCons 0.46
Overall
CADD	11.26	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0751% European (non-Finnish) · 885/1,178,692 alleles

Filtering AF 0.071% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0693%

Overall 0.0604% 974/1,611,694 alleles · ultra-rare exomes 929/1,459,626 · genomes 45/152,068 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0751%	1,332
Remaining individualsnot grpmax-eligible	0.061%	1,640
Admixed American	0.0301%	3,327
South Asian	0.0242%	4,133
African / African-American	0.0133%	7,492
Finnishnot grpmax-eligible	0.00156%	63,936

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.Ala408=
Coding: c.1224C>T
MANE Select: NM_022047
dbSNP: rs138908911
Type: single nucleotide variant
Location: chr6:35319532 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 408: 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); the 'disordered' region

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

Similar variants

DEF6 p.Ala408Thr 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-ala408 (accessed [today's date]).

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