Is DEF6 p.Ser29Cys (c.86C>G) pathogenic?

DEF6 p.Ser29Cys (c.86C>G) is classified Uncertain significance in DEF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-25). AlphaMissense: likely pathogenic (0.9916); Absent from gnomAD v4.1.

How common is DEF6 p.Ser29Cys (c.86C>G) in the general population?

DEF6 p.Ser29Cys (c.86C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DEF6 p.Ser29Cys (c.86C>G)?

AlphaMissense predicts likely pathogenic (score 0.9916) — an in-silico prediction, not a clinical call.

DEF6 p.Ser29Cys

c.86C>G · rs1190132582 · VCV2711458

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9916 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9916	likely pathogenic · top 6% in DEF6
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -9.81	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.70	unconstrained · MANE · 24 kb · p 1.6e-17 · regional, not allelic
Overall
CADD	28.5	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.Ser29Cys
Coding: c.86C>G
MANE Select: NM_022047
dbSNP: rs1190132582
Type: single nucleotide variant
Location: chr6:35297942 (GRCh38)
Gene constraint: LOEUF 0.61 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 78.91

Full DEF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEF6 p.Ser29= Likely benign ★ 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
DEF6 p.Arg349Leu 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-ser29cys (accessed [today's date]).

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