Is DEF8 p.Arg360Cys (c.1078C>T) pathogenic?

DEF8 p.Arg360Cys (c.1078C>T) is classified Uncertain significance in DEF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-13). AlphaMissense: likely benign (0.1346); Ultra-rare (popmax 0.0946%, amr).

How common is DEF8 p.Arg360Cys (c.1078C>T) in the general population?

DEF8 p.Arg360Cys (c.1078C>T) is ultra-rare (popmax 0.0946%, amr) (gnomAD).

What do computational predictors say about DEF8 p.Arg360Cys (c.1078C>T)?

AlphaMissense predicts likely benign (score 0.1346) — an in-silico prediction, not a clinical call.

DEF8 p.Arg360Cys

c.1078C>T · rs138908537 · VCV2369495

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1346 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0946%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1346	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -9.82	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.019 · regional, not allelic
Overall
CADD	27.5	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R421C vs ClinVar R360C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0946% Admixed American · 45/47,544 alleles

Filtering AF 0.0726% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0649%

Overall 0.0336% 494/1,470,462 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0946%	1,057
Middle Eastern	0.053%	1,887
Remaining individualsnot grpmax-eligible	0.0482%	2,075
Ashkenazi Jewishnot grpmax-eligible	0.0409%	2,443
European (non-Finnish)	0.0348%	2,877
South Asian	0.0194%	5,146
African / African-American	0.0134%	7,435

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: DEF8
Protein: p.Arg360Cys
Coding: c.1078C>T
MANE Select: NM_001242818
dbSNP: rs138908537
Type: single nucleotide variant
Location: chr16:89964245 (GRCh38)
Gene constraint: LOEUF 0.928 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 76.04

Full DEF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEF8 p.Arg360His Uncertain significance ★ ⚠ same residue
DEF8 p.Gln29Glu Benign ★★ same type
DEF8 p.Glu122= Benign ★★ same type
DEF8 p.Pro318= Benign ★★ same type
DEF8 p.Val356Met Likely benign ★★ ⚠ same type
DEF8 c.-11+101C>T Uncertain significance ★ ⚠ same type
DEF8 c.-11+104C>T Uncertain significance ★ ⚠ same type
DEF8 c.-11+10G>T 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/def8-p-arg360cys (accessed [today's date]).

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