Is DEFA3 p.Ala75Val (c.224C>T) pathogenic?

DEFA3 p.Ala75Val (c.224C>T) is classified Uncertain significance in DEFA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-17). AlphaMissense: likely benign (0.2355); Ultra-rare (popmax 0.024%, mid).

How common is DEFA3 p.Ala75Val (c.224C>T) in the general population?

DEFA3 p.Ala75Val (c.224C>T) is ultra-rare (popmax 0.024%, mid) (gnomAD).

What do computational predictors say about DEFA3 p.Ala75Val (c.224C>T)?

AlphaMissense predicts likely benign (score 0.2355) — an in-silico prediction, not a clinical call.

DEFA3 p.Ala75Val

c.224C>T · rs565992362 · VCV2381624

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2355 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.024%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2355	likely benign
REVEL	0.065	moderately benign-leaning
SaProt	LLR -6.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.26	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP -14
Regional constraint	o/e 0.14	constrained · MANE · 703 bp · p 3e-11 · regional, not allelic
Overall
CADD	8.303	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.024% Middle Eastern · 1/4,174 alleles

Filtering AF 0.00465% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00422%

Overall 0.0043% 64/1,487,560 alleles · ultra-rare exomes 62/1,347,482 · genomes 2/140,078 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.024%	4,174
European (non-Finnish)	0.00582%	17,188

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: DEFA3
Protein: p.Ala75Val
Coding: c.224C>T
MANE Select: NM_005217
dbSNP: rs565992362
Type: single nucleotide variant
Location: chr8:7016051 (GRCh38)
Gene constraint: LOEUF 0.74 · pLI 0.78 (gnomAD)
Structure: AlphaFold pLDDT 73.70 · 6 PDB

Full DEFA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFA3 p.Ala14Val Uncertain significance ★ ⚠ same type
DEFA3 p.Ala17Asp Uncertain significance ★ ⚠ same type
DEFA3 p.Ala19Ser Uncertain significance ★ ⚠ same type
DEFA3 p.Arg2Gly Uncertain significance ★ same type
DEFA3 p.Arg78Cys Uncertain significance ★ ⚠ same type
DEFA3 p.Arg79His Uncertain significance ★ ⚠ same type
DEFA3 p.Arg88Gly Uncertain significance ★ ⚠ same type
DEFA3 p.Asp50Asn 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/defa3-p-ala75val (accessed [today's date]).

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