Is DEF6 p.Ala617Val (c.1850C>T) pathogenic?

DEF6 p.Ala617Val (c.1850C>T) is classified Uncertain significance in DEF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-13). AlphaMissense: likely benign (0.0704); Ultra-rare (popmax 0.0133%, afr); Associated with immunodeficiency 87 and autoimmunity.

What condition is associated with DEF6 p.Ala617Val (c.1850C>T)?

DEF6 p.Ala617Val (c.1850C>T) is associated with immunodeficiency 87 and autoimmunity (ClinVar).

How common is DEF6 p.Ala617Val (c.1850C>T) in the general population?

DEF6 p.Ala617Val (c.1850C>T) is ultra-rare (popmax 0.0133%, afr) (gnomAD).

What do computational predictors say about DEF6 p.Ala617Val (c.1850C>T)?

AlphaMissense predicts likely benign (score 0.0704) — an in-silico prediction, not a clinical call.

DEF6 p.Ala617Val

c.1850C>T · rs866047183 · VCV1405619

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0704 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

immunodeficiency 87 and autoimmunity

Computational evidence

Protein change
AlphaMissense	0.0704	likely benign
REVEL	0.054	moderately benign-leaning
SaProt	LLR -7.21	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 1.8	GERP 1.8, phastCons 0.9
Regional constraint	o/e 0.70	unconstrained · MANE · 24 kb · p 1.6e-17 · regional, not allelic
Overall
CADD	16.19	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 0.0133% African / African-American · 10/74,930 alleles

Filtering AF 0.00723% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0055%

Overall 0.000805% 13/1,614,006 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0133%	7,493
Admixed American	0.00333%	29,998
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Ala617Val
Coding: c.1850C>T
MANE Select: NM_022047
dbSNP: rs866047183
Type: single nucleotide variant
Location: chr6:35321364 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 617: 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

Disease context

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

Similar variants

DEF6 p.Gly177Arg Uncertain significance ★★ ⚠ same condition
DEF6 p.Glu331Lys 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-ala617val (accessed [today's date]).

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