Is DEF6 p.Thr176Ser (c.527C>G) pathogenic?

DEF6 p.Thr176Ser (c.527C>G) is classified Uncertain significance in DEF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-31). AlphaMissense: likely benign (0.0662); Absent from gnomAD v4.1.

How common is DEF6 p.Thr176Ser (c.527C>G) in the general population?

DEF6 p.Thr176Ser (c.527C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DEF6 p.Thr176Ser (c.527C>G)?

AlphaMissense predicts likely benign (score 0.0662) — an in-silico prediction, not a clinical call.

DEF6 p.Thr176Ser

c.527C>G · rs1444410607 · VCV1715010

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0662 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0662	likely benign
REVEL	0.015	strongly benign-leaning
SaProt	LLR -5.46	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 1.1	GERP -0.004, phastCons 0.001
Regional constraint	o/e 0.70	unconstrained · MANE · 24 kb · p 1.6e-17 · regional, not allelic
Overall
CADD	13.47	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

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.Thr176Ser
Coding: c.527C>G
MANE Select: NM_022047
dbSNP: rs1444410607
Type: single nucleotide variant
Location: chr6:35312405 (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.Thr176= 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-thr176ser (accessed [today's date]).

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