Is DEFA5 p.Arg87His (c.260G>A) pathogenic?

DEFA5 p.Arg87His (c.260G>A) is classified Uncertain significance in DEFA5 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-26). AlphaMissense: likely benign (0.1726); Very rare (popmax 0.00542%, nfe).

How common is DEFA5 p.Arg87His (c.260G>A) in the general population?

DEFA5 p.Arg87His (c.260G>A) is very rare (popmax 0.00542%, nfe) (gnomAD).

What do computational predictors say about DEFA5 p.Arg87His (c.260G>A)?

AlphaMissense predicts likely benign (score 0.1726) — an in-silico prediction, not a clinical call.

DEFA5 p.Arg87His

c.260G>A · rs373926117 · VCV3081284

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1726 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00542%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1726	likely benign
REVEL	0.087	moderately benign-leaning
SaProt	LLR -8.69	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 -20
Regional constraint	o/e 1.54	unconstrained · MANE · 1,263 bp · p 3.7e-09 · regional, not allelic
Overall
CADD	0.416	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 0.00542% European (non-Finnish) · 64/1,179,880 alleles

Filtering AF 0.00435% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00396%

Overall 0.00415% 67/1,613,734 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00542%	18,436
East Asian	0.00223%	44,864
Admixed American	0.00167%	59,996
Remaining individualsnot grpmax-eligible	0.0016%	62,498

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.Arg87His
Coding: c.260G>A
MANE Select: NM_021010
dbSNP: rs373926117
Type: single nucleotide variant
Location: chr8:7055456 (GRCh38)
Gene constraint: LOEUF 1.879 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 70.95 · 12 PDB
Residue 87: a β-strand; 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-arg87his (accessed [today's date]).

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