Is DEFA5 p.Ser35Cys (c.104C>G) pathogenic?

DEFA5 p.Ser35Cys (c.104C>G) is classified Uncertain significance in DEFA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-31). AlphaMissense: likely benign (0.2296); Absent from gnomAD v4.1.

How common is DEFA5 p.Ser35Cys (c.104C>G) in the general population?

DEFA5 p.Ser35Cys (c.104C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DEFA5 p.Ser35Cys (c.104C>G)?

AlphaMissense predicts likely benign (score 0.2296) — an in-silico prediction, not a clinical call.

DEFA5 p.Ser35Cys

c.104C>G · VCV4239187

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2296 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2296	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -10.61	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.99	phastCons 0.008
Regional constraint	o/e 1.54	unconstrained · MANE · 1,263 bp · p 3.7e-09 · regional, not allelic
Overall
CADD	17.48	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DEFA5
Protein: p.Ser35Cys
Coding: c.104C>G
MANE Select: NM_021010
Type: single nucleotide variant
Location: chr8:7056594 (GRCh38)
Gene constraint: LOEUF 1.879 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.95 · 12 PDB

Full DEFA5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFA5 p.Arg71His Benign ★★ ⚠ same type
DEFA5 p.Ala14Gly Uncertain significance ★ ⚠ same type
DEFA5 p.Ala14Thr Uncertain significance ★ ⚠ same type
DEFA5 p.Ala17Ser Uncertain significance ★ ⚠ same type
DEFA5 p.Ala19Val Uncertain significance ★ ⚠ same type
DEFA5 p.Ala29Pro Uncertain significance ★ ⚠ same type
DEFA5 p.Ala29Val Uncertain significance ★ ⚠ same type
DEFA5 p.Ala63Val 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/defa5-p-ser35cys (accessed [today's date]).

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