Is DEFB105A p.Pro34Ser (c.100C>T) pathogenic?

DEFB105A p.Pro34Ser (c.100C>T) is classified Likely benign in DEFB105A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-10-23). AlphaMissense: likely benign (0.0865); Very rare (popmax 0.000171%, nfe).

How common is DEFB105A p.Pro34Ser (c.100C>T) in the general population?

DEFB105A p.Pro34Ser (c.100C>T) is very rare (popmax 0.000171%, nfe) (gnomAD).

What do computational predictors say about DEFB105A p.Pro34Ser (c.100C>T)?

AlphaMissense predicts likely benign (score 0.0865) — an in-silico prediction, not a clinical call.

DEFB105A p.Pro34Ser

c.100C>T · VCV4659322

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0865 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000171%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0865	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	LLR -5.58	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 0.021	GERP -1.6
Regional constraint	o/e 0.11	constrained · MANE · 1,827 bp · p 0.00012 · regional, not allelic
Overall
CADD	1.514	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 0.000171% European (non-Finnish) · 2/1,170,842 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000139% 2/1,437,162 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: DEFB105A
Protein: p.Pro34Ser
Coding: c.100C>T
MANE Select: NM_152250
Type: single nucleotide variant
Location: chr8:7823394 (GRCh38)
Gene constraint: LOEUF 1.566 · pLI 0.47 (gnomAD)
Structure: AlphaFold pLDDT 72.22

Full DEFB105A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFB105A c.200G>T Uncertain significance ★ ⚠ same type
DEFB105A p.Ala27Thr Uncertain significance ★ ⚠ same type
DEFB105A p.Leu29Phe Uncertain significance ★ ⚠ same type
DEFB105A p.Ser37Leu Uncertain significance ★ ⚠ same type
DEFB105A p.Ile4Asn Likely benign ★ ⚠ 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/defb105a-p-pro34ser (accessed [today's date]).

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