Is DEF6 p.Glu331Lys (c.991G>A) pathogenic?

DEF6 p.Glu331Lys (c.991G>A) is classified Uncertain significance in DEF6 (ClinVar, Single submitter, 2 submitters; last evaluated 2022-07-06). AlphaMissense: likely benign (0.1802); Rare (popmax 0.157%, sas); Associated with immunodeficiency 87 and autoimmunity.

What condition is associated with DEF6 p.Glu331Lys (c.991G>A)?

DEF6 p.Glu331Lys (c.991G>A) is associated with immunodeficiency 87 and autoimmunity (ClinVar).

How common is DEF6 p.Glu331Lys (c.991G>A) in the general population?

DEF6 p.Glu331Lys (c.991G>A) is rare (popmax 0.157%, sas) (gnomAD).

What do computational predictors say about DEF6 p.Glu331Lys (c.991G>A)?

AlphaMissense predicts likely benign (score 0.1802) — an in-silico prediction, not a clinical call.

DEF6 p.Glu331Lys

c.991G>A · rs541285645 · VCV1300254

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1802 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.157%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 87 and autoimmunity

Computational evidence

Protein change
AlphaMissense	0.1802	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -8.65	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 12	GERP 1, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 24 kb · p 1.6e-17 · regional, not allelic
Overall
CADD	26.2	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 0.157% South Asian · 138/87,680 alleles

Filtering AF 0.136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.128%

Overall 0.00938% 148/1,578,344 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.157%	635
Middle Eastern	0.0169%	5,934
Remaining individualsnot grpmax-eligible	0.0115%	8,704
East Asian	0.00232%	43,174
European (non-Finnish)	8.59e-05%	1,164,070

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.Glu331Lys
Coding: c.991G>A
MANE Select: NM_022047
dbSNP: rs541285645
Type: single nucleotide variant
Location: chr6:35318247 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 331: 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); a UniProt-annotated variant site (in imd87; affects function in vesicle-mediated protein transport as shown by impaired ctla4 trafficking to cell surface in homozygous patient t cells; decreased interaction with rab11a); the 'disordered' region

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

Disease context

immunodeficiency 87 and autoimmunity — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DEF6 p.Ala617Val Uncertain significance ★★ ⚠ same condition
DEF6 p.Gly177Arg Uncertain significance ★★ ⚠ same condition
DEF6 p.Gln314Ter Pathogenic same condition
DEF6 p.Tyr210Asp Pathogenic same condition
DEF6 p.Leu159fs Likely pathogenic ★ same condition
DEF6 p.Ala395Glu Uncertain significance ★★ ⚠ same type
DEF6 p.Arg104Pro Uncertain significance ★★ ⚠ same type
DEF6 p.Arg104Trp 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-glu331lys (accessed [today's date]).

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