Is DEF6 p.Pro561= (c.1683G>A) pathogenic?

DEF6 p.Pro561= (c.1683G>A) is classified Likely benign in DEF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-20). Ultra-rare (popmax 0.0201%, mid).

How common is DEF6 p.Pro561= (c.1683G>A) in the general population?

DEF6 p.Pro561= (c.1683G>A) is ultra-rare (popmax 0.0201%, mid) (gnomAD).

DEF6 p.Pro561=

c.1683G>A · rs768714712 · VCV2170160

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0201%, mid)

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 -6.3	GERP -3.5
Overall
CADD	6.267	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0201% Middle Eastern · 1/4,982 alleles

Filtering AF 0.00324% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00207%

Overall 0.00236% 38/1,612,062 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0201%	4,982
Remaining individualsnot grpmax-eligible	0.0128%	7,794
Admixed American	0.00834%	11,989
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,590
African / African-American	0.00267%	37,404
East Asian	0.00223%	44,876
European (non-Finnish)	0.0017%	58,993

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.Pro561=
Coding: c.1683G>A
MANE Select: NM_022047
dbSNP: rs768714712
Type: single nucleotide variant
Location: chr6:35321197 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 561: 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.Pro561Leu Uncertain significance ★★ ⚠ same residue
DEF6 p.Pro561Arg 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

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-pro561 (accessed [today's date]).

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