Is DEFB134 p.Cys38Phe (c.113G>T) pathogenic?

DEFB134 p.Cys38Phe (c.113G>T) is classified Uncertain significance in DEFB134 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-25). AlphaMissense: likely pathogenic (0.8851); Very rare (popmax 0.0011%, sas).

How common is DEFB134 p.Cys38Phe (c.113G>T) in the general population?

DEFB134 p.Cys38Phe (c.113G>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DEFB134 p.Cys38Phe (c.113G>T)?

AlphaMissense predicts likely pathogenic (score 0.8851) — an in-silico prediction, not a clinical call.

DEFB134 p.Cys38Phe

c.113G>T · rs1253224660 · VCV2290892

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8851 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8851	likely pathogenic · top 8% in DEFB134
REVEL	0.596	indeterminate
SaProt	LLR -12.73	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.3	phastCons 1
Overall
CADD	22.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.0011% South Asian · 1/91,004 alleles

Overall 6.84e-05% 1/1,461,418 alleles · very rare

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: DEFB134
Protein: p.Cys38Phe
Coding: c.113G>T
MANE Select: NM_001302695
dbSNP: rs1253224660
Type: single nucleotide variant
Location: chr8:11994068 (GRCh38)
Gene constraint: LOEUF 1.672 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 79.84
Residue 38: a disulfide bond

Full DEFB134 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFB134 p.Ala65Val Uncertain significance ★ ⚠ same type
DEFB134 p.Asn35Ser Uncertain significance ★ ⚠ same type
DEFB134 p.Cys32Ser Uncertain significance ★ ⚠ same type
DEFB134 p.His29Asn Uncertain significance ★ ⚠ same type
DEFB134 p.Leu40His Uncertain significance ★ ⚠ same type
DEFB134 p.Leu56Pro Uncertain significance ★ ⚠ same type
DEFB134 p.Lys30Asn Uncertain significance ★ ⚠ same type
DEFB134 p.Lys61Glu 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/defb134-p-cys38phe (accessed [today's date]).

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