Is DEFB136 p.Pro70Arg (c.209C>G) pathogenic?

DEFB136 p.Pro70Arg (c.209C>G) is classified Uncertain significance in DEFB136 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-25). AlphaMissense: ambiguous (0.4398); Very rare (popmax 0.00268%, afr).

How common is DEFB136 p.Pro70Arg (c.209C>G) in the general population?

DEFB136 p.Pro70Arg (c.209C>G) is very rare (popmax 0.00268%, afr) (gnomAD).

What do computational predictors say about DEFB136 p.Pro70Arg (c.209C>G)?

AlphaMissense predicts ambiguous (score 0.4398) — an in-silico prediction, not a clinical call.

DEFB136 p.Pro70Arg

c.209C>G · VCV3500834

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4398 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00268%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4398	ambiguous
REVEL	0.088	moderately benign-leaning
SaProt	LLR -7.45	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP 1.2, phastCons 0.006
Regional constraint	o/e 1.28	unconstrained · MANE · 659 bp · p 0.0053 · regional, not allelic
Overall
CADD	14.72	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 0.00268% African / African-American · 2/74,504 alleles

Filtering AF 0.000446% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000167%

Overall 0.000187% 3/1,602,020 alleles · very rare exomes 3/1,449,796 · genomes 0/152,224 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00268%	37,252
European (non-Finnish)	8.51e-05%	1,174,502

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.Pro70Arg
Coding: c.209C>G
MANE Select: NM_001033018
Type: single nucleotide variant
Location: chr8:11973965 (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-pro70arg (accessed [today's date]).

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