Is DEF8 p.Leu315Phe (c.943C>T) pathogenic?

DEF8 p.Leu315Phe (c.943C>T) is classified Uncertain significance in DEF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-03). AlphaMissense: ambiguous (0.4031); Absent from gnomAD v4.1.

How common is DEF8 p.Leu315Phe (c.943C>T) in the general population?

DEF8 p.Leu315Phe (c.943C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DEF8 p.Leu315Phe (c.943C>T)?

AlphaMissense predicts ambiguous (score 0.4031) — an in-silico prediction, not a clinical call.

DEF8 p.Leu315Phe

c.943C>T · VCV4239163

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4031 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.4031	ambiguous
REVEL	0.138	moderately benign-leaning
SaProt	LLR -6.34	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 12 kb · p 0.019 · regional, not allelic
Overall
CADD	27.1	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 L376F vs ClinVar L315F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DEF8
Protein: p.Leu315Phe
Coding: c.943C>T
MANE Select: NM_001242818
Type: single nucleotide variant
Location: chr16:89963384 (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-leu315phe (accessed [today's date]).

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