Is DEF6 p.Glu358= (c.1074G>A) pathogenic?

DEF6 p.Glu358= (c.1074G>A) is classified Likely benign in DEF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-29). Very rare (popmax 0.000785%, nfe).

How common is DEF6 p.Glu358= (c.1074G>A) in the general population?

DEF6 p.Glu358= (c.1074G>A) is very rare (popmax 0.000785%, nfe) (gnomAD).

DEF6 p.Glu358=

c.1074G>A · VCV3604799

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000785%, 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 1.9	GERP -1.2, phastCons 1
Overall
CADD	10.82	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000785% European (non-Finnish) · 9/1,146,926 alleles

Filtering AF 0.000369% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000267%

Overall 0.000647% 10/1,546,110 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0018%	55,404
European (non-Finnish)grpmax	0.000785%	127,436

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Glu358=
Coding: c.1074G>A
MANE Select: NM_022047
Type: single nucleotide variant
Location: chr6:35318330 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 358: 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-glu358 (accessed [today's date]).

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