Is DEFB135 p.Pro20Ser (c.58C>T) pathogenic?

DEFB135 p.Pro20Ser (c.58C>T) is classified Uncertain significance in DEFB135 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-26). AlphaMissense: likely benign (0.2457); Ultra-rare (popmax 0.0649%, nfe).

How common is DEFB135 p.Pro20Ser (c.58C>T) in the general population?

DEFB135 p.Pro20Ser (c.58C>T) is ultra-rare (popmax 0.0649%, nfe) (gnomAD).

What do computational predictors say about DEFB135 p.Pro20Ser (c.58C>T)?

AlphaMissense predicts likely benign (score 0.2457) — an in-silico prediction, not a clinical call.

DEFB135 p.Pro20Ser

c.58C>T · rs199632993 · VCV2304660

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2457 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0649%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2457	likely benign
REVEL	0.294	indeterminate
SaProt	LLR -6.79	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.6	phastCons 0.32
Regional constraint	o/e 1.43	unconstrained · MANE · 2,266 bp · p 2.7e-05 · regional, not allelic
Overall
CADD	19.14	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 0.0649% European (non-Finnish) · 766/1,180,024 alleles

Filtering AF 0.0611% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0596%

Overall 0.0512% 827/1,613,960 alleles · ultra-rare exomes 774/1,461,850 · genomes 53/152,110 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0649%	1,541
Admixed American	0.045%	2,222
Remaining individualsnot grpmax-eligible	0.0416%	2,403
African / African-American	0.0107%	9,361

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: DEFB135
Protein: p.Pro20Ser
Coding: c.58C>T
MANE Select: NM_001033017
dbSNP: rs199632993
Type: single nucleotide variant
Location: chr8:11982378 (GRCh38)
Gene constraint: LOEUF 1.954 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.04

Full DEFB135 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFB135 p.Pro20Leu Uncertain significance ★ ⚠ same residue
DEFB135 p.Pro20Thr Uncertain significance ★ ⚠ same residue
DEFB135 p.Arg45Gln Uncertain significance ★ ⚠ same type
DEFB135 p.Arg45Trp Uncertain significance ★ ⚠ same type
DEFB135 p.Arg4Gly Uncertain significance ★ ⚠ same type
DEFB135 p.Arg55Cys Uncertain significance ★ ⚠ same type
DEFB135 p.Asn27Ser Uncertain significance ★ ⚠ same type
DEFB135 p.Asp59Val 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/defb135-p-pro20ser (accessed [today's date]).

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