Is DEF6 p.Tyr210Asp (c.628T>G) pathogenic?

DEF6 p.Tyr210Asp (c.628T>G) is classified Pathogenic in DEF6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-10-21). AlphaMissense: likely pathogenic (0.9469); Absent from gnomAD v4.1; Associated with immunodeficiency 87 and autoimmunity.

What condition is associated with DEF6 p.Tyr210Asp (c.628T>G)?

DEF6 p.Tyr210Asp (c.628T>G) is associated with immunodeficiency 87 and autoimmunity (ClinVar).

How common is DEF6 p.Tyr210Asp (c.628T>G) in the general population?

DEF6 p.Tyr210Asp (c.628T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DEF6 p.Tyr210Asp (c.628T>G)?

AlphaMissense predicts likely pathogenic (score 0.9469) — an in-silico prediction, not a clinical call.

DEF6 p.Tyr210Asp

c.628T>G · rs2150387447 · VCV1300255

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9469 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

immunodeficiency 87 and autoimmunity

Computational evidence

Protein change
AlphaMissense	0.9469	likely pathogenic ✓ concordant with ClinVar
REVEL	0.463	indeterminate
SaProt	LLR -12.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 0.97, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 24 kb · p 1.6e-17 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DEF6
Protein: p.Tyr210Asp
Coding: c.628T>G
MANE Select: NM_022047
dbSNP: rs2150387447
Type: single nucleotide variant
Location: chr6:35312506 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 210: a modified residue (phosphotyrosine); a UniProt-annotated variant site (in imd87; affects function in vesicle-mediated protein transport as shown by impaired ctla4 trafficking to cell surface in homozygous patient t cells; severely decreased protein levels in patient t cells; increased protein degradation)

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.Tyr210Ter Uncertain significance ★ same residue
DEF6 p.Ala617Val Uncertain significance ★★ ⚠ same condition
DEF6 p.Gly177Arg Uncertain significance ★★ ⚠ same condition
DEF6 p.Glu331Lys Uncertain significance ★ ⚠ same condition
DEF6 p.Gln314Ter Pathogenic same condition
DEF6 p.Leu159fs Likely pathogenic ★ same condition
DEF6 p.Ala395Glu Uncertain significance ★★ ⚠ same type
DEF6 p.Arg104Pro 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-tyr210asp (accessed [today's date]).

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