Is DEFB1 p.Ser39Thr (c.116G>C) pathogenic?

DEFB1 p.Ser39Thr (c.116G>C) is classified Uncertain significance in DEFB1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-16). AlphaMissense: likely benign (0.0871); Ultra-rare (popmax 0.0668%, eas).

How common is DEFB1 p.Ser39Thr (c.116G>C) in the general population?

DEFB1 p.Ser39Thr (c.116G>C) is ultra-rare (popmax 0.0668%, eas) (gnomAD).

What do computational predictors say about DEFB1 p.Ser39Thr (c.116G>C)?

AlphaMissense predicts likely benign (score 0.0871) — an in-silico prediction, not a clinical call.

DEFB1 p.Ser39Thr

c.116G>C · VCV4239190

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0871 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0871	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -8.87	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 -7.6	GERP -3.4
Regional constraint	o/e 2.11	unconstrained · MANE · 7,173 bp · p 2.7e-22 · regional, not allelic
Overall
CADD	0.065	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 0.0668% East Asian · 30/44,890 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00204% 33/1,614,246 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0668%	1,496
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)	0.000169%	590,023

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: DEFB1
Protein: p.Ser39Thr
Coding: c.116G>C
MANE Select: NM_005218
Type: single nucleotide variant
Location: chr8:6870772 (GRCh38)
Gene constraint: LOEUF 1.969 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.82 · 15 PDB
Residue 39: a disulfide bond; an α-helix

Full DEFB1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFB1 p.Gly27= Benign ★★ same type
DEFB1 p.Ala19Thr Uncertain significance ★ ⚠ same type
DEFB1 p.Ala64Gly Uncertain significance ★ ⚠ same type
DEFB1 p.Asp33Gly Uncertain significance ★ ⚠ same type
DEFB1 p.Cys12Phe Uncertain significance ★ ⚠ same type
DEFB1 p.Cys44Tyr Uncertain significance ★ ⚠ same type
DEFB1 p.Cys59Tyr Uncertain significance ★ ⚠ same type
DEFB1 p.Gly57Ala 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/defb1-p-ser39thr (accessed [today's date]).

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