Is DEFB136 p.Pro69Arg (c.206C>G) pathogenic?

DEFB136 p.Pro69Arg (c.206C>G) is classified Uncertain significance in DEFB136 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-08). AlphaMissense: likely pathogenic (0.7226); Very rare (popmax 0.00417%, nfe).

How common is DEFB136 p.Pro69Arg (c.206C>G) in the general population?

DEFB136 p.Pro69Arg (c.206C>G) is very rare (popmax 0.00417%, nfe) (gnomAD).

What do computational predictors say about DEFB136 p.Pro69Arg (c.206C>G)?

AlphaMissense predicts likely pathogenic (score 0.7226) — an in-silico prediction, not a clinical call.

DEFB136 p.Pro69Arg

c.206C>G · rs199745025 · VCV2469239

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7226 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00417%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7226	likely pathogenic
REVEL	0.091	moderately benign-leaning
SaProt	LLR -8.31	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 1.7	GERP 4.4, phastCons 0.96
Regional constraint	o/e 1.28	unconstrained · MANE · 659 bp · p 0.0053 · regional, not allelic
Overall
CADD	15.98	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 0.00417% European (non-Finnish) · 49/1,175,546 alleles

Filtering AF 0.00319% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00287%

Overall 0.00318% 51/1,604,050 alleles · very rare exomes 45/1,451,900 · genomes 6/152,150 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00417%	23,991
Admixed American	0.00171%	58,346
African / African-American	0.00134%	74,484

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.Pro69Arg
Coding: c.206C>G
MANE Select: NM_001033018
dbSNP: rs199745025
Type: single nucleotide variant
Location: chr8:11973968 (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.Ala7Pro 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

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-pro69arg (accessed [today's date]).

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