Is DEFB134 p.Leu56Pro (c.167T>C) pathogenic?

DEFB134 p.Leu56Pro (c.167T>C) is classified Uncertain significance in DEFB134 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-31). AlphaMissense: likely pathogenic (0.8814); Ultra-rare (popmax 0.0133%, amr).

How common is DEFB134 p.Leu56Pro (c.167T>C) in the general population?

DEFB134 p.Leu56Pro (c.167T>C) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about DEFB134 p.Leu56Pro (c.167T>C)?

AlphaMissense predicts likely pathogenic (score 0.8814) — an in-silico prediction, not a clinical call.

DEFB134 p.Leu56Pro

c.167T>C · rs764105335 · VCV2293300

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8814 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8814	likely pathogenic · top 8% in DEFB134
REVEL	0.283	benign-leaning
SaProt	LLR -13.09	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Overall
CADD	23.1	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 0.0133% Admixed American · 8/59,986 alleles

Filtering AF 0.00662% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00483%

Overall 0.000682% 11/1,613,890 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,498
African / African-American	0.004%	24,978

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: DEFB134
Protein: p.Leu56Pro
Coding: c.167T>C
MANE Select: NM_001302695
dbSNP: rs764105335
Type: single nucleotide variant
Location: chr8:11994014 (GRCh38)
Gene constraint: LOEUF 1.672 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84
Residue 56: a disulfide bond

Full DEFB134 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFB134 p.Ala65Val Uncertain significance ★ ⚠ same type
DEFB134 p.Asn35Ser Uncertain significance ★ ⚠ same type
DEFB134 p.Cys32Ser Uncertain significance ★ ⚠ same type
DEFB134 p.Cys38Phe Uncertain significance ★ ⚠ same type
DEFB134 p.His29Asn Uncertain significance ★ ⚠ same type
DEFB134 p.Leu40His Uncertain significance ★ ⚠ same type
DEFB134 p.Lys30Asn Uncertain significance ★ ⚠ same type
DEFB134 p.Lys61Glu 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/defb134-p-leu56pro (accessed [today's date]).

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