Is DEF8 p.Arg338Trp (c.1012C>T) pathogenic?

DEF8 p.Arg338Trp (c.1012C>T) is classified Uncertain significance in DEF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-31). AlphaMissense: ambiguous (0.5397); Very rare (popmax 0.00333%, amr).

How common is DEF8 p.Arg338Trp (c.1012C>T) in the general population?

DEF8 p.Arg338Trp (c.1012C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about DEF8 p.Arg338Trp (c.1012C>T)?

AlphaMissense predicts ambiguous (score 0.5397) — an in-silico prediction, not a clinical call.

DEF8 p.Arg338Trp

c.1012C>T · rs1184827917 · VCV2553577

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5397 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5397	ambiguous
REVEL	0.649	pathogenic-leaning
SaProt	LLR -11.57	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.33 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.3	GERP -0.24, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.019 · regional, not allelic
Overall
CADD	32.0	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 R399W vs ClinVar R338W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/60,002 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000434% 7/1,613,754 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,001
Remaining individualsnot grpmax-eligible	0.0016%	62,464
European (non-Finnish)	0.000339%	294,991

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.Arg338Trp
Coding: c.1012C>T
MANE Select: NM_001242818
dbSNP: rs1184827917
Type: single nucleotide variant
Location: chr16:89964179 (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-arg338trp (accessed [today's date]).

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