Is DEF8 p.Arg288Ser (c.864G>C) pathogenic?

DEF8 p.Arg288Ser (c.864G>C) is classified Uncertain significance in DEF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-10). AlphaMissense: ambiguous (0.451); Very rare (popmax 0.005%, amr).

How common is DEF8 p.Arg288Ser (c.864G>C) in the general population?

DEF8 p.Arg288Ser (c.864G>C) is very rare (popmax 0.005%, amr) (gnomAD).

What do computational predictors say about DEF8 p.Arg288Ser (c.864G>C)?

AlphaMissense predicts ambiguous (score 0.451) — an in-silico prediction, not a clinical call.

DEF8 p.Arg288Ser

c.864G>C · VCV3500762

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.451 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.451	ambiguous
REVEL	0.086	moderately benign-leaning
SaProt	LLR -5.54	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.41	acceptor loss at this position · masked 0 · deltas
Constraint at this position
Conservation	phyloP -0.21	GERP -3.1, phastCons 0.038
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.019 · regional, not allelic
Overall
CADD	16.73	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R349S vs ClinVar R288S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/60,010 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.00112% 18/1,613,994 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,003
European (non-Finnish)	0.00127%	78,668

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.Arg288Ser
Coding: c.864G>C
MANE Select: NM_001242818
Type: single nucleotide variant
Location: chr16:89962068 (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.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
DEF8 c.-11+113C>A 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-arg288ser (accessed [today's date]).

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