Is DEFB136 p.Asp74Val (c.221A>T) pathogenic?

DEFB136 p.Asp74Val (c.221A>T) is classified Uncertain significance in DEFB136 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-12). AlphaMissense: likely benign (0.1575); Very rare (popmax 8.54e-05%, nfe).

How common is DEFB136 p.Asp74Val (c.221A>T) in the general population?

DEFB136 p.Asp74Val (c.221A>T) is very rare (popmax 8.54e-05%, nfe) (gnomAD).

What do computational predictors say about DEFB136 p.Asp74Val (c.221A>T)?

AlphaMissense predicts likely benign (score 0.1575) — an in-silico prediction, not a clinical call.

DEFB136 p.Asp74Val

c.221A>T · rs2486166754 · VCV2611417

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1575 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.54e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1575	likely benign
REVEL	0.192	benign-leaning
SaProt	LLR -4.72	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 2.7, phastCons 0.02
Regional constraint	o/e 1.28	unconstrained · MANE · 659 bp · p 0.0053 · regional, not allelic
Overall
CADD	12.69	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.54e-05% European (non-Finnish) · 1/1,171,052 alleles

Overall 6.27e-05% 1/1,595,038 alleles · very rare exomes 1/1,442,744 · genomes 0/152,294 · 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.Asp74Val
Coding: c.221A>T
MANE Select: NM_001033018
dbSNP: rs2486166754
Type: single nucleotide variant
Location: chr8:11973953 (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.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-asp74val (accessed [today's date]).

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