Is DEF6 p.Arg461Ser (c.1383A>T) pathogenic?

DEF6 p.Arg461Ser (c.1383A>T) is classified Uncertain significance in DEF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-08). AlphaMissense: ambiguous (0.4742); Absent from gnomAD v4.1.

How common is DEF6 p.Arg461Ser (c.1383A>T) in the general population?

DEF6 p.Arg461Ser (c.1383A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DEF6 p.Arg461Ser (c.1383A>T)?

AlphaMissense predicts ambiguous (score 0.4742) — an in-silico prediction, not a clinical call.

DEF6 p.Arg461Ser

c.1383A>T · rs1164229591 · VCV2616991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4742 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4742	ambiguous
REVEL	0.188	benign-leaning
SaProt	LLR -9.23	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.30	acceptor loss at this position · masked 0 · deltas
Pangolin	Δ0.23	loss · gain 0.07 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 0.088	GERP -3.3, phastCons 0.36
Regional constraint	o/e 0.70	unconstrained · MANE · 24 kb · p 1.6e-17 · regional, not allelic
Overall
CADD	17.77	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.Arg461Ser
Coding: c.1383A>T
MANE Select: NM_022047
dbSNP: rs1164229591
Type: single nucleotide variant
Location: chr6:35319819 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91
Residue 461: 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-arg461ser (accessed [today's date]).

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