Is DEF6 p.Leu348= (c.1042C>T) pathogenic?

DEF6 p.Leu348= (c.1042C>T) is classified Benign in DEF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-02-04). Common (popmax 13.7%, afr) — too common for a highly-penetrant pathogenic allele.

DEF6 p.Leu348=

Q: How common is DEF6 p.Leu348= (c.1042C>T) in the general population?

DEF6 p.Leu348= (c.1042C>T) is common (popmax 13.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1042C>T · rs61748597 · VCV1165992

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 13.7%, afr) — too common for a highly-penetrant pathogenic allele

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 0.41	GERP -0.29, phastCons 0.99
Overall
CADD	11.85	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 13.7% African / African-American · 10,063/73,436 alleles

Filtering AF 13.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.4%

Overall 2.04% 31,679/1,556,038 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	13.7%	7
Middle Eastern	2.24%	45
Remaining individualsnot grpmax-eligible	2%	50
European (non-Finnish)	1.66%	60
Admixed American	1.57%	64
Ashkenazi Jewishnot grpmax-eligible	0.578%	173
Finnishnot grpmax-eligible	0.254%	393
South Asian	0.123%	813

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.Leu348=
Coding: c.1042C>T
MANE Select: NM_022047
dbSNP: rs61748597
Type: single nucleotide variant
Location: chr6:35318298 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 348: 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-leu348 (accessed [today's date]).

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