Is DEFB136 p.Ala7Pro (c.19G>C) pathogenic?

DEFB136 p.Ala7Pro (c.19G>C) is classified Uncertain significance in DEFB136 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-15). AlphaMissense: likely benign (0.0863); Very rare (popmax 8.47e-05%, nfe).

How common is DEFB136 p.Ala7Pro (c.19G>C) in the general population?

DEFB136 p.Ala7Pro (c.19G>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about DEFB136 p.Ala7Pro (c.19G>C)?

AlphaMissense predicts likely benign (score 0.0863) — an in-silico prediction, not a clinical call.

DEFB136 p.Ala7Pro

c.19G>C · rs1333197898 · VCV2618753

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0863 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0863	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -11.10	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.015	GERP 3.3
Regional constraint	o/e 1.28	unconstrained · MANE · 659 bp · p 0.0053 · regional, not allelic
Overall
CADD	4.876	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 8.47e-05% European (non-Finnish) · 1/1,179,982 alleles

Overall 6.2e-05% 1/1,614,080 alleles · very rare exomes 1/1,461,812 · genomes 0/152,268 · joint denominator

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: DEFB136
Protein: p.Ala7Pro
Coding: c.19G>C
MANE Select: NM_001033018
dbSNP: rs1333197898
Type: single nucleotide variant
Location: chr8:11974581 (GRCh38)
Gene constraint: LOEUF 1.968 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 82.09

Full DEFB136 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFB136 p.Ala38Pro Uncertain significance ★ ⚠ same type
DEFB136 p.Arg66His Uncertain significance ★ ⚠ same type
DEFB136 p.Asp26His Uncertain significance ★ ⚠ same type
DEFB136 p.Asp74Val Uncertain significance ★ ⚠ same type
DEFB136 p.Gln71Glu Uncertain significance ★ ⚠ same type
DEFB136 p.Gly21Cys Uncertain significance ★ ⚠ same type
DEFB136 p.Gly43Arg Uncertain significance ★ ⚠ same type
DEFB136 p.His78Leu 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/defb136-p-ala7pro (accessed [today's date]).

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