Is DEF6 p.Glu514= (c.1542G>A) pathogenic?

DEF6 p.Glu514= (c.1542G>A) is classified Benign in DEF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-04). Low-frequency (popmax 4.55%, afr).

How common is DEF6 p.Glu514= (c.1542G>A) in the general population?

DEF6 p.Glu514= (c.1542G>A) is low-frequency (popmax 4.55%, afr) (gnomAD).

DEF6 p.Glu514=

c.1542G>A · rs61734578 · VCV1170886

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

low-frequency (popmax 4.55%, afr)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.33	donor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP 3.2	GERP -1.5, phastCons 1
Overall
CADD	9.73	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 4.55% African / African-American · 3,384/74,390 alleles

Filtering AF 4.42% ClinGen BA1/BS1 input FAF95, joint · FAF99 4.37%

Overall 2.04% 32,008/1,565,576 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	4.82%	21
African / African-Americangrpmax	4.55%	22
Ashkenazi Jewishnot grpmax-eligible	4.05%	25
Middle Eastern	3.37%	30
Remaining individualsnot grpmax-eligible	2.29%	44
European (non-Finnish)	2.07%	48
Admixed American	1.67%	60
Finnishnot grpmax-eligible	1.05%	95
South Asian	0.52%	192
East Asian	0.0743%	1,345

Amish 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.Glu514=
Coding: c.1542G>A
MANE Select: NM_022047
dbSNP: rs61734578
Type: single nucleotide variant
Location: chr6:35319978 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 514: 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.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-glu514 (accessed [today's date]).

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