Is DEF8 p.Asp403Asn (c.1207G>A) pathogenic?

DEF8 p.Asp403Asn (c.1207G>A) is classified Uncertain significance in DEF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-01-03). AlphaMissense: likely pathogenic (0.9755); Very rare (popmax 0.00401%, nfe).

How common is DEF8 p.Asp403Asn (c.1207G>A) in the general population?

DEF8 p.Asp403Asn (c.1207G>A) is very rare (popmax 0.00401%, nfe) (gnomAD).

What do computational predictors say about DEF8 p.Asp403Asn (c.1207G>A)?

AlphaMissense predicts likely pathogenic (score 0.9755) — an in-silico prediction, not a clinical call.

DEF8 p.Asp403Asn

c.1207G>A · rs148949111 · VCV2211179

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9755 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9755	likely pathogenic
REVEL	0.197	benign-leaning
SaProt	LLR -10.60	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.8	GERP 0.59, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.019 · regional, not allelic
Overall
CADD	29.8	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 D464N vs ClinVar D403N) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00401% European (non-Finnish) · 47/1,171,730 alleles

Filtering AF 0.00309% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00277%

Overall 0.00313% 50/1,595,180 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00401%	24,930
East Asian	0.0023%	43,506
African / African-American	0.00134%	74,404
South Asian	0.00114%	88,096

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.Asp403Asn
Coding: c.1207G>A
MANE Select: NM_001242818
dbSNP: rs148949111
Type: single nucleotide variant
Location: chr16:89964529 (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-asp403asn (accessed [today's date]).

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