Is DEFA6 p.Glu35Asp (c.105G>C) pathogenic?

DEFA6 p.Glu35Asp (c.105G>C) is classified Benign in DEFA6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-25). AlphaMissense: likely benign (0.1407); Common (popmax 6.39%, afr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about DEFA6 p.Glu35Asp (c.105G>C)?

AlphaMissense predicts likely benign (score 0.1407) — an in-silico prediction, not a clinical call.

DEFA6 p.Glu35Asp

Q: How common is DEFA6 p.Glu35Asp (c.105G>C) in the general population?

DEFA6 p.Glu35Asp (c.105G>C) is common (popmax 6.39%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.105G>C · rs113837602 · VCV776283

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1407 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 6.39%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1407	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5	GERP -2.5
Regional constraint	o/e 1.60	unconstrained · MANE · 1,214 bp · p 4.4e-11 · regional, not allelic
Overall
CADD	4.348	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.39% African / African-American · 4,788/74,978 alleles

Filtering AF 6.23% ClinGen BA1/BS1 input FAF95, joint · FAF99 6.17%

Overall 0.335% 5,413/1,614,016 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	6.39%	16
Remaining individualsnot grpmax-eligible	0.469%	213
Admixed American	0.417%	240
Middle Eastern	0.264%	379
South Asian	0.011%	9,103
European (non-Finnish)	0.00466%	21,455
East Asian	0.00223%	44,890

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: DEFA6
Protein: p.Glu35Asp
Coding: c.105G>C
MANE Select: NM_001926
dbSNP: rs113837602
Type: single nucleotide variant
Location: chr8:6925931 (GRCh38)
Gene constraint: LOEUF 1.911 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 67.49 · 5 PDB

Full DEFA6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DEFA6 p.Ala14Asp Uncertain significance ★ ⚠ same type
DEFA6 p.Ala24Thr Uncertain significance ★ ⚠ same type
DEFA6 p.Ala33Gly Uncertain significance ★ ⚠ same type
DEFA6 p.Ala38Val Uncertain significance ★ ⚠ same type
DEFA6 p.Ala57Thr Uncertain significance ★ ⚠ same type
DEFA6 p.Ala63Pro Uncertain significance ★ ⚠ same type
DEFA6 p.Arg2Lys Uncertain significance ★ ⚠ same type
DEFA6 p.Arg42Cys 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/defa6-p-glu35asp (accessed [today's date]).

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