Is DEFB129 p.Pro6Ser (c.16C>T) pathogenic?

DEFB129 p.Pro6Ser (c.16C>T) is classified Uncertain significance in DEFB129 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-28). AlphaMissense: likely pathogenic (0.7607); Rare (popmax 0.197%, mid).

How common is DEFB129 p.Pro6Ser (c.16C>T) in the general population?

DEFB129 p.Pro6Ser (c.16C>T) is rare (popmax 0.197%, mid) (gnomAD).

What do computational predictors say about DEFB129 p.Pro6Ser (c.16C>T)?

AlphaMissense predicts likely pathogenic (score 0.7607) — an in-silico prediction, not a clinical call.

DEFB129 p.Pro6Ser

c.16C>T · rs375610686 · VCV3081324

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7607 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.197%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7607	likely pathogenic · top 7% in DEFB129
REVEL	0.064	moderately benign-leaning
SaProt	LLR -8.58	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 1.7, phastCons 0.94
Regional constraint	o/e 0.82	unconstrained · MANE · 2,479 bp · p 0.0067 · regional, not allelic
Overall
CADD	21.4	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

Grpmax group 0.197% Middle Eastern · 12/6,082 alleles

Filtering AF 0.114% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0892%

Overall 0.00967% 156/1,613,966 alleles · rare exomes 133/1,461,812 · genomes 23/152,154 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.197%	507
Ashkenazi Jewishnot grpmax-eligible	0.0642%	1,558
Remaining individualsnot grpmax-eligible	0.0304%	3,288
Admixed American	0.0267%	3,750
South Asian	0.00988%	10,120
African / African-American	0.00667%	14,985
European (non-Finnish)	0.00644%	15,526

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: DEFB129
Protein: p.Pro6Ser
Coding: c.16C>T
MANE Select: NM_080831
dbSNP: rs375610686
Type: single nucleotide variant
Location: chr20:227304 (GRCh38)
Gene constraint: LOEUF 1.476 · pLI 0.22 (gnomAD)
Structure: AlphaFold pLDDT 60.57

Full DEFB129 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFB129 p.Ala163Val Uncertain significance ★ ⚠ same type
DEFB129 p.Arg26Cys Uncertain significance ★ ⚠ same type
DEFB129 p.Arg26His Uncertain significance ★ ⚠ same type
DEFB129 p.Asn73Lys Uncertain significance ★ ⚠ same type
DEFB129 p.Asp154His Uncertain significance ★ ⚠ same type
DEFB129 p.Glu178Asp Uncertain significance ★ ⚠ same type
DEFB129 p.Glu182Lys Uncertain significance ★ ⚠ same type
DEFB129 p.Glu20Ala 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/defb129-p-pro6ser (accessed [today's date]).

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