Is ENDOU p.Asp228= (c.684C>T) pathogenic?

ENDOU p.Asp228= (c.684C>T) is classified Benign in ENDOU (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-07-16). Common (popmax 7.99%, afr) — too common for a highly-penetrant pathogenic allele.

ENDOU p.Asp228=

Q: How common is ENDOU p.Asp228= (c.684C>T) in the general population?

ENDOU p.Asp228= (c.684C>T) is common (popmax 7.99%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.684C>T · rs61734364 · VCV784236

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 7.99%, afr) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.8	GERP -4.1
Overall
CADD	0.267	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 7.99% African / African-American · 5,996/75,006 alleles

Filtering AF 7.82% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.76%

Overall 0.433% 6,996/1,614,076 alleles · common exomes 3,582/1,461,838 · genomes 3,414/152,238 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	7.99%	13
Admixed American	0.503%	199
Remaining individualsnot grpmax-eligible	0.499%	200
Middle Eastern	0.365%	274
European (non-Finnish)	0.0286%	3,491
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,935
South Asian	0.0176%	5,692
East Asian	0.00668%	14,959
Finnishnot grpmax-eligible	0.00156%	64,030

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: ENDOU
Protein: p.Asp228=
Coding: c.684C>T
MANE Select: NM_001172439
dbSNP: rs61734364
Type: single nucleotide variant
Location: chr12:47716367 (GRCh38)
Gene constraint: LOEUF 1.094 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.91 · 1 PDB
Residue 228: an α-helix; the endou domain

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

Similar variants

ENDOU p.Asp228Gly Uncertain significance ★ ⚠ same residue
ENDOU p.Arg211Gln Benign ★★ same type
ENDOU p.Tyr317= Benign ★★ same type
ENDOU c.551+1G>A Uncertain significance ★ same type
ENDOU p.Ala229Val Uncertain significance ★ ⚠ same type
ENDOU p.Ala402Thr Uncertain significance ★ ⚠ same type
ENDOU p.Ala404Pro Uncertain significance ★ ⚠ same type
ENDOU p.Ala78Asp 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/endou-p-asp228 (accessed [today's date]).

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