Is DEFA5 p.Arg75Cys (c.223C>T) pathogenic?

DEFA5 p.Arg75Cys (c.223C>T) is classified Uncertain significance in DEFA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: likely pathogenic (0.6442); Ultra-rare (popmax 0.0329%, mid).

How common is DEFA5 p.Arg75Cys (c.223C>T) in the general population?

DEFA5 p.Arg75Cys (c.223C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about DEFA5 p.Arg75Cys (c.223C>T)?

AlphaMissense predicts likely pathogenic (score 0.6442) — an in-silico prediction, not a clinical call.

DEFA5 p.Arg75Cys

c.223C>T · rs140349881 · VCV2225181

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6442 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6442	likely pathogenic
REVEL	0.079	moderately benign-leaning
SaProt	LLR -10.45	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 -7.9
Regional constraint	o/e 1.54	unconstrained · MANE · 1,263 bp · p 3.7e-09 · regional, not allelic
Overall
CADD	2.404	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00291% 47/1,613,680 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
Admixed American	0.02%	4,998
African / African-American	0.00801%	12,483
Remaining individualsnot grpmax-eligible	0.0032%	31,235
East Asian	0.00223%	44,874
European (non-Finnish)	0.00195%	51,300
South Asian	0.0011%	90,996

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: DEFA5
Protein: p.Arg75Cys
Coding: c.223C>T
MANE Select: NM_021010
dbSNP: rs140349881
Type: single nucleotide variant
Location: chr8:7055493 (GRCh38)
Gene constraint: LOEUF 1.879 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.95 · 12 PDB
Residue 75: a disulfide bond

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-arg75cys (accessed [today's date]).

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