Is DEFB136 p.Ala38Pro (c.112G>C) pathogenic?

DEFB136 p.Ala38Pro (c.112G>C) is classified Uncertain significance in DEFB136 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-23). AlphaMissense: likely pathogenic (0.8395); Ultra-rare (popmax 0.033%, mid).

How common is DEFB136 p.Ala38Pro (c.112G>C) in the general population?

DEFB136 p.Ala38Pro (c.112G>C) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about DEFB136 p.Ala38Pro (c.112G>C)?

AlphaMissense predicts likely pathogenic (score 0.8395) — an in-silico prediction, not a clinical call.

DEFB136 p.Ala38Pro

c.112G>C · VCV3839293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8395 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8395	likely pathogenic
REVEL	0.123	moderately benign-leaning
SaProt	LLR -13.84	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 5	GERP 6.5, phastCons 1
Regional constraint	o/e 1.28	unconstrained · MANE · 659 bp · p 0.0053 · regional, not allelic
Overall
CADD	21.0	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 0.033% Middle Eastern · 2/6,058 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00999%

Overall 0.011% 177/1,608,482 alleles · ultra-rare exomes 153/1,456,284 · genomes 24/152,198 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	0.768%	130
Middle Easterngrpmax	0.033%	3,029
Admixed American	0.0203%	4,925
Remaining individualsnot grpmax-eligible	0.0145%	6,920
European (non-Finnish)	0.0123%	8,121
African / African-American	0.00134%	74,672
South Asian	0.00111%	89,918

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala38Pro
Coding: c.112G>C
MANE Select: NM_001033018
Type: single nucleotide variant
Location: chr8:11974062 (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.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
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-ala38pro (accessed [today's date]).

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